Micellar Casein by Fit Foods Manufacturing Ltd.

LIKELY EFFECTIVE

• Atopic dermatitis (eczema). Consuming casein peptide as part of formula with or without breastmilk for up to 6 months reduces the risk of atopic dermatitis in infants. Details: Clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4-6 months, reduces the risk for atopic dermatitis during the first 9-24 months of life by 52% to 73% when compared to cow's milk formula (91655,91656,91658). The benefits of casein peptides appear to be most significant in infants with a family history of atopy (91655,91656). Additionally, the benefit of using a casein peptide-based formula during the first 4 months of life persists into childhood, with a 29% reduced risk of developing atopic dermatitis at 6 years of age when compared to cow's milk formula (91659,91660). Clinical research also shows that casein peptide formula is equally effective to hydrolyzed whey protein formula for reducing the risk for atopic dermatitis in infants (91657,91658,91659,91660,91661).
• Atopic disease. Consuming casein peptide as part of formula during the first 4 months of life reduces the risk of atopic disease in infants with a family history of atopy. The benefits of casein peptide in infants without a family history of atopy is unclear. Details: Clinical research in infants with a family history of atopy shows that taking a casein peptide-based formula (Nutramigen, Mead Johnson) during the first 4 months of life, or after weaning from breastmilk, reduces the risk for atopic manifestations during the first 12-18 months of life by 39% to 44% when compared with cow's milk formula (91656,91658). This benefit persists over time, with a 20% reduced risk for developing atopic disease at 6 years of age when compared to cow's milk formula (91660). However, it may not be beneficial in children without a family history of atopy. One large, ancillary clinical study in children at increased risk for development of type 1 diabetes, but not specifically at risk for atopy, shows that using an extensively hydrolyzed casein peptide formula (Nutramigen, Mead Johnson) in infancy for up to 6-8 months does not prevent persistent asthma, allergic rhinitis, or atopic dermatitis development when compared with using a conventional formula containing 80% intact cow's milk protein and 20% hydrolyzed milk protein (Enfamil, Mead Johnson). The validity of these findings is limited by the patient population and the unclear duration of follow up (106564).
• Food allergies. Consuming casein peptide formulas is a safe alternative to cow's milk in children with cow's milk allergy. Details: Clinical research shows that specific casein peptide formulas are a safe and well-tolerated alternative for children with documented allergy to cow's milk. Evaluated formulas include Alimentum (Abbot Laboratories), Damira 2000 (Nutrition & Sante S.L.), Frisolac Allergycare (Friesland Nutrition), and Nutramigen (Mead Johnson) (91663,91664,91665,111439). A cost-effective analysis in children with cow's milk allergy also suggests that using casein peptide-based formula is cost-effective dominant and reduces other allergic manifestations when compared with soy-based formula (111438).

POSSIBLY EFFECTIVE

• Colic. Clinical research shows that consuming casein peptides as part of formula reduces crying, short-term, in infants with colic. Details: Clinical research in infants with colic shows that replacing cow's milk formula with a specific casein peptide formula (Nutramigen, Mead Johnson) significantly reduces crying and colic when compared with cow's milk formula. However, this effect appears to diminish after more than four days of use (91262). Preliminary clinical research shows that consuming specific casein peptide formulas (Alimentum, Abbot Laboratories; Nutramigen, Mead Johnson) for 7 days reduces daily crying time by up to 5 hours and reduces crying intensity when compared with baseline in infants with colic (91264). The validity of this finding is limited by the lack of a comparator group.
• Diabetes. Consuming casein peptides with carbohydrates may be beneficial for reducing postprandial glucose and insulin levels in adults with type 2 diabetes. Casein peptides have also been evaluated for the prevention of type 1 diabetes in infants, with inconclusive results. Details: In adults with type 2 diabetes, casein protein may improve postprandial glucose levels. Most clinical research shows that consuming casein peptides in conjunction with a carbohydrate bolus increases postprandial insulin response by 26% to 300% and reduces postprandial glucose levels by 5% to 28% when compared with consuming carbohydrates alone (91276,91295,91297,91299). These effects seem to persist with casein peptide doses as low as 12 grams daily, but not 6 grams daily (91300). Preliminary clinical research also shows that adding leucine 5 grams or 0.1 grams/kg to casein peptides increases postprandial insulin levels by 52% to 200%, reduces postprandial glucose levels by 5% to 12%, and improves 24-hour glucose levels by 11% when compared with consuming carbohydrates alone (91296,91297). However, some preliminary clinical research shows that consuming casein peptides 0.4 grams/kg with each meal for one day does not improve glycemic control (91298). These differing outcomes might be related to the forms of carbohydrates used, which include carbohydrate boluses and carbohydrate-containing meals. Additionally, the evidence for the effects of intact casein protein, as opposed to casein peptides, on postprandial insulin and glucose levels is conflicting (91276,91299). Clinical research in infants 6-8 months of age who are genetically predisposed to type 1 diabetes shows that administering a specific casein peptide-based formula (Nutramigen, Mead Johnson) in place of breastmilk decreases the development of one or more diabetes-associated auto-antibodies when compared with cow's milk formula. However, there was no difference in type 1 diabetes incidence after 10 years. This study was not powered to detect a difference in this outcome (91675).
• Hypertension. The casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), sometimes referred to as lactotripeptides, can modestly reduce blood pressure in patients with hypertension. Lower doses given for shorter durations seem to produce greater effects, and the effects may be more pronounced in Japanese patients than in European patients. Details: The most comprehensive meta-analysis to-date in patients with hypertension shows that taking casein peptides reduces systolic blood pressure (SBP) by 3 mmHg and diastolic blood pressure (DBP) by 1.5 mmHg. The average dose of casein peptides was 10.5 mg daily, including IPP 5.2 mg and VPP 5.3 mg daily, for about 8 weeks. However, there may be an inverse dose-response relationship; daily doses of casein peptides of 10 mg or less, lasting for 8 weeks or less, reduced blood pressure to a greater degree when compared with higher doses given for longer durations. Furthermore, casein peptides produced by fermentation resulted in modestly greater blood pressure reduction when compared with casein peptides produced by enzymatic hydrolysis (103765). Patient ethnicity may also play a role in the magnitude of effect. Other meta-analyses show a 1-6 mmHg reduction in SBP and 0.6-1.5 mmHg reduction in DBP when compared with control (103762,103763,103765,111437). A small clinical study in healthy Japanese males and postmenopausal adults with prehypertension shows that supplementation with casein peptides IPP 2 mg and VPP 1.4 mg daily for 8 weeks reduces home-monitored 7-day mean DBP, but not SBP, by 0.9 mmHg, compared with an increase of 1.2 mmHg in those receiving placebo (106565). Although findings are positive overall, the validity of the above meta-analysis, as well as older or less comprehensive analyses, is limited by the poor reporting and methodology of the included studies (103763,103765,103770,103772). Some limited research in patients with metabolic syndrome shows conflicting blood pressure lowering effects. A small clinical study shows that taking IPP/VPP (Calpis Co., Ltd.) 10.2 mg in the morning before breakfast daily for 4 weeks lowers 24-hour ambulatory systolic blood pressure by 2 mmHg, but not diastolic blood pressure, when compared with placebo (103764). However, another study shows that taking casein peptides 5-25 mg daily with plant sterols 2 grams daily orally for 12 weeks does not reduce blood pressure when compared with placebo (103767). Notably, this study was not adequately powered to detect small changes in blood pressure.
• Neonatal jaundice. Clinical research suggests that consuming casein peptide reduces the risk of jaundice in neonates. Details: Preliminary clinical research shows that feeding newborns a specific casein peptide formula (Nutramigen, Mead Johnson) for 3 weeks reduces the risk of jaundice when compared with whey-predominant formula (91642) or human milk (91642,91651). Other preliminary clinical research in breastfed newborns shows that taking 5 mL of casein peptide formula, created by enzymatic hydrolysis, 6 times daily for 7 days decreases transcutaneous bilirubin levels when compared with breastfeeding alone (91643).

POSSIBLY INEFFECTIVE

• Asthma. Consuming casein peptide does not appear to reduce the risk of asthma in infants. Details: Most clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4 months, does not reduce the risk for asthma in the first 4 months to 6 years of life in children with a family history of atopy (91655,91659,91660). However, one preliminary clinical study shows that feeding infants Nutramigen beginning at about 3.8 months of age decreases wheezing by 61% compared to cow's milk formula; the incidence of asthma was not evaluated (91656).
• Infant development. Consuming casein peptide does not appear to affect growth or development in healthy infants, or in premature or low-birth weight infants. Details: Most clinical research shows that using casein peptide-predominant formula for 6 weeks to 6 months in premature, low-birth weight, or healthy infants does not affect growth when compared with breast milk, whey protein-based formula, rice hydrolysate formula, cow's milk formula, or amino acid-based formula (86085,91644,91672,91673). Additionally, feeding infants a specific casein peptide formula (Nutramigen, Mead Johnson) for 4 months does not affect growth at 6 or 10 years when compared with whey protein-based formula, cow's milk formula, or breast milk (86085,91644). However, clinical research suggests that a casein peptide-based formula might be beneficial in infants with cow's milk allergy. One study in this population shows that casein peptide-based formula significantly increases growth from 6-12 months of age when compared with soy-based formula (91672).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral casein peptides are beneficial in patients with acne. Details: Preliminary clinical research in adults with moderate to severe acne shows that taking a specific casein peptide (Lactium) 150 mg orally daily for 84 days does not reduce acne lesion count when compared with control. However, the study may have been inadequately powered to detect a difference between groups (111436).
• Aging skin. It is unclear if oral casein peptides are beneficial in patients with aging skin. Details: A small clinical study in healthy, normotensive older Japanese adults shows that taking casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) orally once daily for 48 weeks reduces facial pigmentation area by about 15%, compared with an increase of about 6% in patients taking placebo (106563).
• Anxiety. Although there has been interest in using oral casein peptides for anxiety, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Athletic performance. It is unclear if oral casein peptides are beneficial for athletic performance. Details: Preliminary clinical research in overweight male police officers shows that taking casein peptides 1.5 grams/kg orally daily in two divided doses for 12 weeks, in conjunction with resistance training, decreases body fat percentage by 3%, increases lean body mass by 2 kg, and improves chest, shoulder, and leg press strength by around 30% when compared with whey protein (85648).
• Cancer. Although there has been interest in using oral casein peptides for cancer, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Diarrhea. It is unclear if oral casein peptides are beneficial in patients with diarrhea. Details: Preliminary clinical research in male children with persistent diarrhea shows that consuming a casein peptide-based diet during hospitalization is less effective for reducing stool output than a yogurt-based diet (91648).
• Epilepsy. Although there has been interest in using oral casein peptides for epilepsy, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Exercise-induced muscle soreness. It is unclear if oral casein peptides are beneficial in patients with exercise-induced muscle soreness. Details: Preliminary clinical research in male cyclists shows that drinking 200 mL of a carbohydrate beverage containing 1.8% casein peptides every 5 km followed by 500 mL after cycling completion reduces exercise-induced muscle soreness and improves late-exercise time-trial performance when compared with drinking a carbohydrate beverage alone (91256).
• Fatigue. Although there has been interest in using oral casein peptides for fatigue, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Hyperlipidemia. Low quality research suggests that oral casein peptides are not beneficial in patients with hyperlipidemia. Details: A meta-analysis of randomized trials in subjects with and without hyperlipidemia shows that using casein peptide-based diets for 1-48 weeks does not improve low-density lipoprotein cholesterol, high-density cholesterol, or triglyceride levels when compared with control (111437).
• Insomnia. It is unclear if oral casein peptides are beneficial in patients with insomnia. Details: A small clinical study in Korean patients with poor sleep quality shows that taking a specific product (Lactium, Ingredia) containing bovine alpha-s1 casein peptides 300 mg one hour before bedtime for 4 weeks modestly improves sleep efficiency based on subjective reports and actigraphy measures when compared with placebo (103774). Casein peptides have also been studied as part of combination products. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, and L-theanine 50 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). It is unclear if these effects are due to L-theanine, alpha-s1-casein tryptic hydrolysate, or the combination.
• Physical performance. It is unclear if oral casein peptides are beneficial for physical performance. Details: Preliminary clinical research in healthy older males shows that taking casein peptides 10 grams before and after resistance training for 8 weeks does not improve strength or body composition when compared with placebo (91255).
• Stress. Although there has been interest in using oral casein peptides for stress, there is insufficient reliable information about the clinical effects of casein peptides for this purpose. More evidence is needed to rate casein peptides for these uses.

(Read more about CASEIN PEPTIDES)

EFFECTIVE

• Lactose intolerance. Lactase is effective for reducing gastrointestinal symptoms from consuming lactose in lactose intolerant individuals. Details: Multiple clinical trials show that taking lactase orally is effective for reducing GI symptoms in lactose-intolerant people when used before the consumption of lactose or when added to milk prior to consumption (2371,2372,2373,106669).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colic. It is unclear if oral lactase is beneficial in infants with colic. Details: Preliminary clinical research in infants with colic shows that supplementing human milk or formula with lactase (Crosscare Ltd) for 10 days reduces breath hydrogen levels, but not time spent crying, when compared with placebo. However, approximately 30% of infants in this study were considered to be noncompliant. When only infants considered to be compliant were included in the analysis, time spent crying during the 10-day treatment period was reduced by about 6 hours in the lactase group when compared with placebo (96347). In two other small trials, giving 5 drops of a specific lactase formulation (Colibid, RG Pharmaceutica or Yamoo, Walter Bushnell) to infants aged 0-6 months with colic before each feed, or 4 times a day, for 2-4 weeks significantly reduces crying time and fussing time when compared with placebo (104107,112190). However, measures of crying time were based on subjective parent recall only.
• Prematurity. It is unclear if oral lactase is beneficial in premature patients. Details: Clinical research shows that giving fortified human milk or preterm formula treated with lactase drops (Lactaid, McNeil Consumer Products Company) to preterm infants does not improve weight gain, feeding tolerance, weekly length gain, or gain in head circumference by 36 weeks' gestational age or discharge from the hospital (whichever comes first) when compared with giving untreated milk or formula (96346). More evidence is needed to rate lactase for these uses.

(Read more about LACTASE)

LIKELY INEFFECTIVE

• Alzheimer disease. Lecithin does not improve daily functioning in patients with Alzheimer disease. Details: In patients with Alzheimer disease, taking various types of lecithin, 1.2-45 grams daily for up to 6 months, alone or in combination with various conventional medications, does not improve cognitive function or other measures of disease progression (5149,5151,5152,5156,14817,14823,14825,14837,14838).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral lecithin can slow age-related cognitive decline. Details: A small clinical crossover study in healthy adults aged 64 years and older shows that taking lecithin 26 grams orally daily, alone or in combination with physostigmine, for 5 weeks does not seem to improve memory when compared with placebo (19204).
• Anxiety. Although there is interest in using oral lecithin for anxiety, there is insufficient reliable information about the clinical effects of lecithin for this condition.
• Atopic dermatitis (eczema). Although there is interest in using oral lecithin for atopic dermatitis, there is insufficient reliable information about the clinical effects of lecithin for this condition.
• Bipolar disorder. It is unclear if oral lecithin is beneficial in patients with bipolar disorder. Details: A clinical study in six patients with mania shows that taking lecithin 10 mg three times daily improves symptoms of delusions, incoherent speech, and hallucinations when compared with placebo (14839).
• Dry skin. Although there is interest in using topical lecithin for dry skin, there is insufficient reliable information about the clinical effects of lecithin for this condition.
• Friedreich ataxia. Small clinical studies suggest that oral lecithin is not beneficial in people with Friedreich ataxia. Details: Preliminary clinical research shows that taking lecithin 25 grams orally daily for 1 month does not have any benefit in people with Friedreich ataxia (59298). Other preliminary clinical research shows that taking lecithin for a longer period of 6 months also does not improve performance (19211).
• Hyperlipidemia. Although lecithin may lower cholesterol in healthy people, it does not seem to improve cholesterol levels in people with hyperlipidemia. Details: Some clinical research shows that taking lecithin 20-30 grams daily for up to 11 months decreases cholesterol in healthy people (5147,14820). However, other clinical research shows that lecithin has no effect on low-density lipoprotein cholesterol or total cholesterol levels in people with hyperlipidemia (5148,14820).
• Parkinson disease. It is unclear if oral lecithin is beneficial in patients with Parkinson disease. Details: Preliminary clinical research in patients with Parkinson disease shows that taking lecithin 32 grams daily for 8 weeks does not improve symptoms when compared with placebo (19212).
• Postoperative pain. It is unclear if oral lecithin is beneficial for reducing postoperative pain. Details: Preliminary clinical research shows that taking lecithin 20 grams prior to surgery increases choline levels, but does not reduce postoperative pain after gynecological surgery, when compared with placebo (91231).
• Tardive dyskinesia. It is unclear if oral lecithin is beneficial in patients with tardive dyskinesia. Details: Two small clinical studies in patients with tardive dyskinesia shows that taking lecithin orally for 2 months, alone or in combination with lithium, does not improve symptoms when compared with placebo (14822,14824).
• TPN-associated hepatic steatosis. It is unclear if oral lecithin is beneficial in patients with hepatic steatosis associated with long-term total parenteral nutrition (TPN). Details: A small clinical study in patients on long-term TPN with low choline levels suggests that taking lecithin 20 grams orally twice daily for 6 weeks reduces the degree of hepatic steatosis, compared with no significant changes in those taking placebo (5140).
• Ulcerative colitis. Oral lecithin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a disease-specific medical food (Profermin, Nordisk Rebalance) containing lecithin, fermented oats, barley malt, and lactobacillus plantarum, as 250 mL twice daily for 24 weeks, decreases disease activity by over 56% when compared with baseline and leads to remission in 46% of patients with mild-to-moderate ulcerative colitis (91228). Other preliminary clinical research in this population shows that taking Profermin 250 mL twice daily for 8 weeks improves disease activity and remission rate when compared with another medical food (Fresubin Original, Fresenius Kabi) (90271). The effects of lecithin alone are unclear. More evidence is needed to rate lecithin for these uses.

(Read more about LECITHIN)

EFFECTIVE

• Hypokalemia. Oral or intravenous potassium can treat and prevent hypokalemia. Details: Administering potassium orally or intravenously is effective for treating and preventing hypokalemia (15,107970). Oral potassium 20 mEq (780 mg of elemental potassium) is typically taken once daily to prevent hypokalemia (15,95010). Oral potassium 40-100 mEq (1560-3900 mg of elemental potassium) is typically taken in 2-5 divided doses daily to treat hypokalemia (95010). Doses should be limited to 40 mEq (1560 mg of elemental potassium), and the total dose should not exceed 200 mEq (7800 mg of elemental potassium) in 24 hours (95010). Potassium supplementation and route of administration should be individualized based on serum potassium level and patient status (15,107970).

LIKELY EFFECTIVE

• Hypertension. Oral potassium, via dietary intake or supplementation, reduces blood pressure. Details: Population research has found that higher dietary potassium consumption is associated with a lower risk of developing hypertension (1310,8817,69512). Additionally, most clinical research shows that potassium, taken orally as part of the diet or as a supplement, reduces systolic blood pressure by about 3-9.5 mmHg and diastolic blood pressure by about 2-6.4 mmHg in patients with or without hypertension (3385,92104,92106,95624,107974). In most of these studies, daily intake of potassium typically ranged from about 1500-7800 mg, with the most common intake being about 2340-2540 mg daily (92104,95624). However, some research shows that taking potassium does not lower systolic or diastolic blood pressure (69541,69550,107966). Differences in the patient populations, potassium intake, and salt intake could have contributed to the conflicting results. Potassium seems to be more effective for people with hypertension, low potassium levels, high daily sodium intake, and for Black adults (3384,3385,3386,92104,92106). Some research also shows that the greatest blood pressure-lowering effects of potassium occur at doses of about 3900-7800 mg daily (95624). A meta-analysis of clinical trials using a novel computational technique to assess both potassium intake and excretion suggests that the optimal blood pressure reduction occurs when taking about 1500 mg supplemental potassium daily or an overall intake of 4500-6500 mg potassium daily (105448). This analysis is limited by the heterogeneity and short duration of the included trials. There is also interest in utilizing low-sodium, high-potassium food substitutes to treat hypertension. Research shows that using salt substitutes containing 25% to 30% potassium chloride reduces systolic and diastolic blood pressure by 3-4.6 mmHg and 1 mmHg, respectively, when compared with regular table salt (107971,107976). In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines recommending that patients with hypertension consume 3500-5000 mg of potassium daily (95680). This intake of potassium is expected to lower systolic blood pressure by about 4-5 mmHg in patients with hypertension and by about 2 mmHg in normotensive patients (3385). Although potassium supplements and dietary potassium both seem to be beneficial, the guidelines recommend getting potassium from dietary sources, since potassium-rich diets are usually heart-healthy (95680). Additionally, the US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Kidney stones (nephrolithiasis). Oral prescription potassium citrate reduces the risk of kidney stone recurrence. It is unclear if non-prescription potassium citrate would be beneficial. Details: The American Urological Association (AUA) recommends potassium citrate therapy for patients with recurrent calcium stones and low urinary citrate, those with recurrent calcium or calcium oxalate stones without current metabolic abnormalities, and those with uric acid or cystine stones. The citrate component reduces urine calcium excretion and increases urine citrate and urine pH, which in turn alleviates crystal growth, formation, and aggregation. Sodium citrate may also be used to prevent stone recurrence; however, due to sodium's propensity to increase urine calcium excretion, potassium citrate remains the preferred salt formulation (107972). It is important to note that potassium citrate supplements are not equivalent to prescription potassium citrate products. Dose and duration of treatment is determined by a healthcare professional and individualized based on a patient's urinary citrate levels (107975,107989). Serum potassium levels should be monitored prior to starting potassium citrate, within 2 weeks of treatment initiation, and every 12 months (107975).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Eating foods high in potassium and low in sodium might reduce the risk of cardiovascular disease. It is unclear if taking potassium supplements has the same benefit. Details: Large population studies in adults without prior CVD have found that higher dietary potassium intake is associated with a lower risk of cardiovascular events (109395,109399). One study found that daily potassium intake of about 3300 mg is associated with a 13% reduction in CVD risk when compared with intake of about 1920 mg (109399). The other study found that each additional 1000 mg of daily urinary potassium excretion, which is a marker of dietary intake, is associated with an 18% reduction in CVD risk (109395). Another observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Stroke. Eating foods high in potassium and low in sodium might reduce the risk of stroke. It is unclear if taking potassium supplements has the same benefit. Details: Higher dietary intake of potassium seems to be associated with a lower risk of stroke. Population research has found that increasing dietary potassium intake by 1-1.5 grams daily is associated with up to a 20% reduced risk of stroke (92105,92107). Some population research has found that higher supplemental intake of potassium is associated with a 29% reduced risk of ischemic stroke. However, supplemental potassium intake is not found to be associated with a lower risk of hemorrhagic or total stroke (92107). An observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental hypersensitivity. It is unclear if topical potassium improves dental hypersensitivity. Details: One meta-analysis of clinical research shows that using a dentifrice containing 5% potassium nitrite reduces dentin sensitivity when compared with a dentifrice that does not contain potassium nitrite (69549). Other clinical research published in a systematic review shows that potassium-containing toothpastes might reduce dentin sensitivity more than controls that do not contain potassium. However, these toothpastes might be less effective than other active toothpastes, such as those containing sodium monofluorophosphate, and the effect may result from a placebo effect, since the mechanism of action of potassium is unclear (69456).
• Diabetes. It is unclear if increasing dietary potassium reduces the risk of diabetes. Details: A meta-analysis of 7 large population studies has found that consuming dietary potassium 3300-3500 mg daily is associated with a 20% reduction in the risk of diabetes when compared with consumption below 1000 mg daily. Results were similar when studies that measured potassium intake with a dietary questionnaire were analyzed separately from those that measured intake based on urinary potassium excretion (110776). However, the validity of this finding is limited by the heterogeneity of the included studies. Furthermore, despite use of data from various databases, most studies included in the analysis were conducted by the same author.
• Impaired glucose tolerance (prediabetes). It is unclear if oral potassium improves glycemic control in prediabetes. Details: A small clinical study in Black patients with prediabetes shows that taking extended-release potassium (Klor-Con M10, Cardinal Health) 40 mEq daily as potassium chloride for 3 months does not improve glucose tolerance when compared with placebo. Although fasting glucose levels were slightly reduced in the potassium group when compared with placebo, both groups experienced a worsening of glucose intolerance, with no change in insulin levels or glycated hemoglobin (98533).
• Osteoporosis. Although there is interest in using oral potassium for osteoporosis, there is insufficient reliable information about the clinical effects of potassium for this condition.
• Physical performance. It is unclear if oral potassium improves physical performance in older adults. Details: Observational research in older adults has found that decreased dietary potassium intake and increased dietary sodium intake over 5 years is associated with worsened physical performance (105450).
• Systemic lupus erythematosus (SLE). It is unclear if oral potassium is beneficial in patients with SLE. Details: Observational research in patients with SLE has found that increased dietary potassium intake is not associated with improvements in disease activity scores or markers of cardiovascular disease, including lipid levels and blood pressure, when compared with low dietary potassium intake. However, higher potassium intake does seem to reduce the odds of having elevated levels of C-reactive protein, a marker of inflammation, in these patients (109397). More evidence is needed to rate potassium for these uses.

(Read more about POTASSIUM)

LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

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LIKELY SAFE ...when used orally and appropriately. Casein peptides have been safely used in clinical trials lasting up to 5 months (85648,103763,103764,103765,103770,103772).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Casein peptide formulas have been safely used in healthy, premature, and very low birth weight infants (91262,91264,91643,91673,91675).

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

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LIKELY SAFE ...when used orally and appropriately with lactose-containing foods. Lactase has Generally Recognized as Safe (GRAS) status in the US when prepared from Candida pseudotropicalis or Kluyveromyces lactis (104108,104109). Lactase has been used safely in doses up to 9900 international units (IU) and up to 13,500 food chemical codex (FCC) units (2371,2372,2373,106669).

CHILDREN: LIKELY SAFE
when used orally and appropriately with lactose-containing foods.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately with lactose-containing foods.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Lecithin has Generally Recognized As Safe (GRAS) status in the US (2619,105544). ...when used orally and appropriately in medicinal amounts. Lecithin has been used safely in doses of up to 30 grams daily for up to 6 weeks (5140,5149,5152,5156,14817,14822,14838,19212). ...when used topically (4914).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts. Lecithin has Generally Recognized As Safe (GRAS) status in the US (105544). There is insufficient reliable information available about the safety of medicinal amounts of lecithin during pregnancy or lactation; avoid using.

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LIKELY SAFE ...when used orally in doses up to 100 mEq total potassium daily, not to exceed 200 mEq in a 24-hour period (95010,107989). Oral potassium chloride and potassium citrate are FDA-approved prescription products (95010,107989). Larger doses increase the risk of hyperkalemia (15). ...when administered intravenously (IV) at appropriate infusion rates (95011). Parenteral potassium is an FDA-approved prescription product (15,95011). A tolerable upper intake level (UL) for potassium has not been established; however, potassium levels should be monitored in individuals at increased risk for hyperkalemia, such as those with kidney disease, heart failure, and adrenal insufficiency (100310,107966).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established for healthy individuals (6243,100310).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 40-80 mEq daily (15). A tolerable upper intake level (UL) has not been established for healthy individuals (100310).

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LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, combining these casein peptides with antihypertensive drugs might increase the risk of hypotension.  Details Clinical research shows that some casein peptides, including the lactotripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), can modestly reduce blood pressure in patients with hypertension (103763,103765,103770,103772).

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ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ACEIs with high doses of potassium increases the risk of hyperkalemia.  Details ACEIs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Using ARBs with high doses of potassium increases the risk of hyperkalemia.  Details ARBs block the actions of the renin-angiotensin-aldosterone system and reduce potassium excretion (95628). Concomitant use of these drugs with potassium supplements increases the risk of hyperkalemia (15,23207). However, concomitant use of these drugs with moderate dietary potassium intake (about 3775-5200 mg daily) does not increase serum potassium levels (95628).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = C Concomitant use increases the risk of hyperkalemia.  Details Using potassium-sparing diuretics with potassium supplements increases the risk of hyperkalemia (15).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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General ...Orally, casein peptides are well tolerated in infants and adults. Adverse effects reported in clinical trials did not occur more frequently than with placebo.

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General ...Orally, lactase is generally well tolerated.

Immunologic ...A case of lactase-induced contact dermatitis and immunoglobulin E (IgE)-mediated allergic rhinoconjunctivitis has been reported in a worker exposed to powdered lactase. Allergy to lactase was confirmed by prick test, open application test, and chamber challenge test (96348).

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General ...Orally, lecithin is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, fullness, and nausea.

Dermatologic ...Orally, lecithin can cause allergic skin reactions in people with egg or soy allergies (15705).

Gastrointestinal ...Orally, lecithin may cause abdominal pain, diarrhea, fullness, and nausea (5140,6243,14817,14822,14838,19204,59281).

Neurologic/CNS ...Orally, lecithin caused CNS complaints and agitation in one patient in a clinical trial (59261).

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General ...Orally or intravenously, potassium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, belching, diarrhea, flatulence, nausea, and vomiting.
Serious Adverse Effects (Rare):
All ROAs: High potassium levels can cause arrhythmia, heart block, hypotension, and mental confusion.

Cardiovascular ...Orally or intravenously, high potassium levels can cause hypotension, cardiac arrhythmias, heart block, or cardiac arrest (15,16,3385,95011,95626,95630).

Gastrointestinal ...Orally or intravenously, high doses of potassium can cause, nausea, vomiting, abdominal pain, diarrhea, and flatulence (95010,95011). Bleeding duodenal ulcers have also been associated with ingestion of slow-release potassium tablets (69625,69672).

Neurologic/CNS ...Orally or intravenously, high potassium levels can cause paresthesia, generalized weakness, flaccid paralysis, listlessness, vertigo, or mental confusion (15,16,3385,95011).

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General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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