GlycoJect Watermelon by Evogen

POSSIBLY EFFECTIVE

• Diabetes. Oral fenugreek seed seems to improve glycemic control in type 2 diabetes. Details: Meta-analyses of 10-14 clinical trials in patients with type 2 diabetes or other metabolic conditions show that taking fenugreek lowers fasting glucose by approximately 14-23 mg/dL, 2-hour postprandial glucose by 21-23 mg/dL, and glycated hemoglobin (HbA1c) by 0.6-1.2% when compared with placebo. The most effective doses and formulations seem to include powdered seed or debitterized seed powder 5-100 grams daily, taken as capsules or added to meals, for up to 3 years or seed hydroalcoholic extract about 1 gram daily for up to 2 months (90112,96065,105016,111503,113499,112120). The validity of these effects is limited by high heterogeneity and low quality in the included studies. Most research also shows that fenugreek seed lowers total cholesterol levels and triglycerides in patients with diabetes, but has inconsistent effects on low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol (96065,102252). Some research shows that taking fenugreek in combination with other ingredients also seems to improve glycemic indices in people with diabetes. These combination products have combined fenugreek with guar gum and gymnema (10284) or millets and legumes (9784). Limited research has also evaluated fenugreek in type 1 diabetes. In one small clinical study, taking 50 grams of defatted fenugreek seed powder twice daily with meals for 10 days reduced 24-hour urine glucose levels by 54% when compared to baseline (622). The validity of this finding is limited by the lack of a comparator group.
• Dysmenorrhea. Oral fenugreek seed might help to reduce menstrual pain. Details: Clinical research in adults with moderate to severe dysmenorrhea shows that taking fenugreek seed powder 1800-2700 mg three times daily for the first 3 days of menstruation followed by 900 mg three times daily for the remainder of two menstrual cycles reduces pain severity when compared with placebo. Patients taking fenugreek seed powder showed a reduction in pain severity of 3.22, compared with a reduction of only 0.18 in the placebo group (90116).
• Sexual arousal. Oral fenugreek seed might help to improve sexual arousal. Details: Clinical research shows that taking a specific fenugreek seed extract (Testofen, Gencor Pacific Ltd) 600 mg daily for 12 weeks increases sexual function by 15% over baseline, compared with no change in the placebo group; the main benefits were in sexual arousal and drive. Morning erection and sexual frequency also improve by 2- to 3-fold (93419). Another clinical study in healthy males shows that taking the same fenugreek seed extract 600 mg daily in combination with magnesium 34 mg, zinc 30 mg, and vitamin B6 10 mg for 6 weeks, improves a composite of symptoms such as sexual cognition, sexual arousal, sexual behavior, and orgasm. The overall improvement in the composite score was 23%, compared with a worsening in the placebo group (93421).
• Sexual dysfunction. Oral fenugreek seed extract might help to improve sexual dysfunction. Details: Clinical research shows that taking a specific fenugreek seed extract (Libifem, Gencor Pacific Ltd.) 300 mg twice daily for two menstrual cycles improves sexual function in healthy pre-menopausal adults with low sex drive. In one clinical trial, overall improvement based on a composite of symptoms was 26% in the fenugreek group, compared with only 2% in the placebo group. Individual scores for sexual cognition, arousal, behavior, drive, and orgasm were all improved. Patients taking fenugreek also had an increased frequency of sexual activity from 1-2 times per month to once per week, compared to no change in the placebo group (93420). Other clinical research in males aged 35-60 years with symptomatic hypogonadism shows that taking a specific fenugreek seed extract (Furosap; Chemical Resources) 500 mg daily after breakfast for 12 weeks improves sexual arousal, mental alertness, and mood when compared with baseline. This fenugreek seed extract was fortified with 20% protodioscin; the other constituents were not specified (108700). The validity of this finding is limited by the lack of comparator group.

POSSIBLY INEFFECTIVE

• Benign prostatic hyperplasia (BPH). Oral fenugreek extract does not seem to improve BPH symptoms. Details: A clinical study in healthy adults with BPH shows that taking a specific fenugreek extract (Testofen, Bluegum Pharmaceuticals) 300 mg twice daily for 12 weeks does not improve BPH symptoms when compared with placebo (102253).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. Although there is interest in using oral fenugreek for alopecia areata, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Alzheimer disease. It is unclear if oral fenugreek seed extract is beneficial for Alzheimer disease. Details: A moderate-sized study in adults with mild to moderate Alzheimer disease shows that taking fenugreek seed extract 5 mL daily for 4 months modestly improves memory but does not improve depression or quality of life measures when compared with placebo (113498).
• Athletic performance. It is unclear if oral fenugreek seed is beneficial for improving athletic performance. Details: Two small clinical studies in resistance-trained young males shows that taking a fenugreek supplement (AI or Torabolic, Indus Biotech) 500 mg daily for 8 weeks in addition to training 4 days every week, decreases body fat by about 2% and sometimes increases leg and bench press performance, but does not improve power, when compared with placebo (18352,18353). Another small study in healthy males undergoing strength training also shows that taking a specific fenugreek extract enriched in furostanol glycosides (Fenu-FG, Indus Biotech Private Limited) 300 mg twice daily for 8 weeks might help to modestly increase the number of bench press repetitions, but not overall strength, when compared with placebo (93423).
• Atopic dermatitis (eczema). Although there is interest in using topical fenugreek for eczema, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Cough. Although there is interest in using oral fenugreek for cough, there is insufficient reliable information about the clinical effects of fenugreek for this purpose.
• Gastroesophageal reflux disease (GERD). It is unclear if oral fenugreek fiber is beneficial for improving heartburn symptoms. Details: A small clinical study in patients with frequent heartburn shows that taking a specific fenugreek fiber product (FenuLife, Frutarom Belgium), 2 grams twice daily 30 minutes before the two biggest meals of the day, improves heartburn after one week of treatment and continuing through the 2-week study period. Fenugreek seemed to be similarly effective to ranitidine 75 mg twice daily (17372).
• Gout. Although there is interest in using topical fenugreek for gout, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Hyperlipidemia. Small clinical studies suggest that oral fenugreek supplements might be beneficial for improving lipid levels. Details: Overall, fenugreek powdered seed seems to modestly reduce lipid levels in people with or without hyperlipidemia; however, most studies have been low-quality, small, and exploratory. Meta-analyses of these studies show that fenugreek reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol (103283,103284). Powdered fenugreek seed has been studied in doses of 0.5-100 grams daily for 10 days to 3 years. While some studies show modest improvement, others show no benefit (622,7389,9783,18359,18361,18362,102252,103283,103284,113497).
• Hypertension. Analysis of small clinical studies suggests that oral fenugreek might slightly improve systolic blood pressure (SBP). Details: A meta-analysis of 6 small clinical studies in healthy adults or those with diabetes, prediabetes, or metabolic syndrome shows that taking fenugreek seed 0.5-50 grams daily for 6-144 weeks reduces SBP by 3.5 mmHg but does not improve diastolic blood pressure (DBP) when compared with placebo. However, subgroup analysis suggests that taking fenugreek at a dose of 15 grams or more daily or for a duration of 12 weeks or less modestly reduces DBP (112110).
• Impaired glucose tolerance (prediabetes). It is unclear if oral fenugreek is beneficial in patients with prediabetes. Details: A small clinical study in adults with prediabetes shows that taking a specific fenugreek seed extract (Trigogen, Gencor Pacific Ltd.) 250 mg twice daily for 12 weeks reduces fasting blood glucose and postprandial blood glucose but not glycated hemoglobin (HbA1c), fasting insulin, or postprandial insulin when compared with placebo (113497). Another small clinical trial in patients with prediabetes shows that taking fenugreek seed extract 200 mg, bergamot extract 500 mg, and olive leaf extract 100 mg daily for 6 months does not improve glycated hemoglobin or fasting blood glucose when compared with placebo (102251).
• Joint pain. Although there is interest in using oral fenugreek for joint pain, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Lactation. Small clinical studies suggest that oral fenugreek, either as a supplement or tea, might increase lactation. Details: A network meta-analysis of 4 small clinical trials shows that taking fenugreek shortly after delivery may modestly increase breast milk production when compared with placebo. Patients in the included studies took fenugreek 1-2 grams as capsules or tea up to 3 times daily for 21-244 days. In most cases, fenugreek treatment was initiated one or two days after delivery. However, fenugreek might be less beneficial for breast milk production when compared with the natural ingredients Indian borage or palm date (96067). Fenugreek has also been used in combination with other ingredients. A small clinical study suggests that drinking a specific herbal tea containing fenugreek. hibiscus, fennel, rooibos, vervain, raspberry, goat's rue, and fennel oil (Humana Still-Tee, Humana, Germany) 200 mL three times daily modestly increases milk production when compared with placebo (22569). Another study in exclusively breastfeeding parents of 2-month-old infants shows that eating lactation cookies containing fenugreek, oatmeal, brewer's yeast, and flaxseed meal daily for 30 days do not improve milk production, perceived insufficiency, or breastfeeding self-efficacy when compared with control (112116).
• Male infertility. It is unclear if oral fenugreek seed is beneficial for improving sperm quality in males with infertility. Details: A small clinical study in healthy male patients ages 20-30 years with oligospermia shows that taking fenugreek seed oil 12 macro drops orally three times daily for 4 months improves sperm count from 6.2 million to 20.1 million, increases sperm motility from 43% to 61%, and reduces sperm abnormality from 68% to 53% when compared with baseline. However, taking the remaining fenugreek seed components 10 grams three times daily for 4 months does not seem to have this effect (90119). The validity of this finding is limited by the lack of a comparator group.
• Menopausal symptoms. It is unclear if oral fenugreek seed is beneficial for improving menopausal symptoms. Details: A small clinical study in perimenopausal patients shows that taking a specific fenugreek seed extract (FenuSMART) 250 mg, standardized to protodioscin 10.3%, trigonelline 3.1%, and total saponin 42.6%, twice daily with meals for 42 days does not improve menopausal symptoms when compared with placebo. However, there was a non-significant trend to reduced hot flashes, night sweats, depression, and insomnia in the treatment group (105000). This study was funded by the supplement manufacturer.
• Metabolic syndrome. It is unclear if oral fenugreek seed is beneficial for metabolic syndrome. Details: A meta-analysis of 29 small clinical studies in healthy adults or those with type 2 diabetes or other metabolic conditions shows that taking fenugreek at doses ranging from 25 mg to 60 grams daily for up to 144 weeks reduces fasting blood glucose by 17 mg/dL, triglycerides by 20 mg/dL, waist circumference by 2.5 cm, and systolic blood pressure by 3.5 mmHg and increases high-density lipoprotein cholesterol by 3.5 mg/dL when compared with control. However, no effect was found on diastolic blood pressure or body mass index (113500).
• Muscle strength. It is unclear if oral fenugreek seed is beneficial for increasing muscle strength. Details: A small study in healthy, active males shows that taking fenugreek seed extract 400 mg or 500 mg daily for 60 days increases grip strength when compared with placebo (103285).
• Myalgia. Although there is interest in using topical fenugreek for myalgia, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Obesity. Small clinical studies suggest that oral fenugreek seed or fiber may increase satiety and decrease caloric intake. Details: Two small clinical studies in overweight and normal weight males shows that taking fenugreek seed extract modestly reduces daily fat intake. At a dose of 392 mg three times daily for 2-6 weeks, fat intake is reduced by 13% to 17%. However, a lower dose of 196 mg three times daily appears to be ineffective. Neither of the doses affect weight, appetite, or satiety (18348,18349). Another small clinical study in obese adults shows that adding 8 grams of fenugreek fiber powder (FenuLife, Frutarom Inc) to a low-calorie beverage increases feelings of satiety and decreases hunger and lunchtime food intake. A lower dose of 4 grams appears to be less effective for reducing hunger but was considered to be more palatable (18350).
• Parkinson disease. It is unclear if oral fenugreek seed is beneficial for Parkinson disease symptoms. Details: One small clinical study in patients with Parkinson disease who are also using levodopa shows that taking fenugreek seed extract (Indus Biotech Private Limited, Pune) 300 mg twice daily for 6 months does not seem to improve behavioral or motor symptoms when compared with placebo (90113).
• Peptic ulcers. Although there is interest in using oral fenugreek for peptic ulcers, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Polycystic ovary syndrome (PCOS). It is unclear if oral fenugreek seed is beneficial for PCOS. Details: A small clinical study in adults with symptomatic PCOS shows that adding a specific fenugreek seed extract (Goldarou Pharmaceutical Co.) 500 mg twice daily to metformin for 8 weeks does not improve insulin resistance, insulin sensitivity, or other symptoms when compared with placebo and metformin (90117). However, other small clinical studies in adults with PCOS show that taking another specific fenugreek seed extract (Furocyst, Cepham Inc.) 1000 mg, enriched with 40% furostanolic saponins, daily for 90 days is associated with a reduction in ovarian cyst size in 46% of patients, complete dissolution in 36% of patients, normalization of menstrual cycles in 71% to 80% of patients, and subsequent pregnancy in 12% of patients. Further, this extract appears to reduce mean cyst size by 42% to 45%, the number of cysts by 38%, ovary volume by 24% to 40%, and hirsutism by 27% while reducing luteinizing hormone, follicle-stimulating hormone, free testosterone, and prolactin and improving liver function and the severity of PCOS-associated ailments including insulin resistance and dyslipidemia (93422,112112,113502). The validity of some of these findings is limited by the lack of a comparator group. Furthermore, this study was funded by the supplement manufacturer.
• Vaginitis. There is limited evidence on the topical use of fenugreek cream in patients with atrophic vaginitis. Details: One small clinical study in postmenopausal patients with atrophic vaginitis shows that administration of 0.5 grams of fenugreek 5% cream intravaginally twice weekly for 12 weeks reduces symptoms of atrophic vaginitis and reduces vaginal pH when compared to baseline. However, fenugreek was not as effective as vaginal cream containing conjugated estrogens (103286). Another small clinical study in postmenopausal patients with vaginal atrophy shows that applying a fenugreek cream 5% intravaginally daily for 8 weeks seems to reduce dyspareunia and vaginal dryness and increase vaginal maturation when compared with a placebo cream (105023).
• Wound healing. Although there is interest in using topical fenugreek for wound healing, there is insufficient reliable information about the clinical effects of fenugreek for this purpose. More evidence is needed to rate fenugreek for these uses.

(Read more about FENUGREEK)

POSSIBLY EFFECTIVE

• Athletic performance. Small studies show that taking a single oral dose of L-citrulline before anaerobic resistance exercise might reduce exhaustion and improve some performance measures. It is unclear if L-citrulline improves aerobic exercise performance; results are conflicting. Details: A meta-analysis of small clinical trials in healthy trained and untrained adults shows that taking L-citrulline prior to mostly anaerobic exercise marginally reduces perceived exhaustion and muscle soreness when compared with placebo (105965). Another meta-analysis including some of the same clinical studies shows that taking L-citrulline malate before exercise modestly increases performance on resistance exercises by an average of 6% when compared with placebo (105968). Individual studies show mixed benefit and mostly use a single dose of L-citrulline malate 8 grams 1 hour before exercise; other studies used L-citrulline 3.3-6 grams mixed in watermelon juice or sucrose water or L-citrulline malate 12 grams given 1-2 hours before exercise (94966,94957,97395,105965). L-citrulline has also been evaluated for use with aerobic exercise. A small study in healthy young adults taking L-citrulline 9 grams in 3 divided doses over 24 hours or as a single dose of 3 grams 3 hours before a treadmill test does not improve performance, but might reduce time to exhaustion, when compared with placebo (16473). Another small clinical study in healthy adults shows that taking about 6.8 grams (100 mg/kg) of L-citrulline daily for 5 days prior to a cycling trial does not improve time to exhaustion, oxygen uptake, or lactate levels when compared with taking 3 grams of glucose as placebo (105964). However, two small clinical trials in healthy males show that taking L-citrulline 2.4-6 grams daily for 7 days prior to a cycling test improves peak power by 9%, total work by 7%, and cycling time trial performance by 1.5% when compared with placebo (94954,94965). Differences in methods of testing athletic performance, the form and dose of L-citrulline used, and/or the duration of supplementation may explain the mixed results. L-citrulline has also been evaluated in combination with L-arginine. Research in male soccer players shows that taking L-citrulline 1.2 grams and L-arginine 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956).

POSSIBLY INEFFECTIVE

• Sarcopenia. Oral L-citrulline does not seem beneficial for muscle strength in older adults when added to structured exercise. Details: Two small clinical studies in older adults show that taking L-citrulline in conjunction with structured exercise does not improve measures of strength, endurance, speed, or balance when compared with placebo and structured exercise (110146,110148). One study evaluated otherwise healthy adults aged 60-73 years taking L-citrulline 3 grams daily for 6 weeks (110146). The other study evaluated older adults with obesity and an average age of 68.5 years taking a specific L-citrulline product (Citrage) 10 grams daily for 12 weeks (110148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Although there is interest in using oral L-citrulline for CVD, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Dementia. Although there is interest in using oral L-citrulline for dementia, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Diabetes. It is unclear if oral L-citrulline is beneficial in patients with diabetes. Details: A small clinical study in adults with diabetes who are taking metformin and sulfonylureas shows that adding L-citrulline (Bulk Supplements Co., Ltd.) 3 grams daily before breakfast for 8 weeks reduces average fasting blood glucose levels by 22 mg/dL and glycated hemoglobin by 0.7%, but does not affect lipid levels, when compared with taking a microcrystalline cellulose placebo (105963).
• Erectile dysfunction (ED). It is unclear if oral L-citrulline is beneficial in patients with ED. Details: A small non-randomized crossover study in adults with mild ED shows that taking L-citrulline 1.5 grams daily for one month improves erection hardness from "mild dysfunction" to "normal function" in 50% of patients, compared with only 8% of patients taking placebo (94956). L-citrulline has also been evaluated in combination with other ingredients. A clinical study in middle-aged males with ED shows that taking a specific combination product (Revactin, MD Concepts LLC) containing L-citrulline, muira puama, ginger root, and guarana twice daily for 3 months improves scores related to erectile function and intercourse satisfaction, but does not improve sexual desire or orgasmic function scores, when compared to baseline (103224). The validity of this study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Another small clinical study in adults with ED living in Japan and using PDE5 inhibitors as needed shows that taking an adjunct 50 mL drink containing L-citrulline 800 mg, a specific fenugreek extract (Testofen) 600 mg, resveratrol 300 mg, and caffeine 40 mg daily for 14 days modestly improves erectile function and satisfaction with intercourse and orgasm when compared with a placebo drink (105966). The validity of this finding may be confounded by the "as needed" use of PDE5 inhibitors, which was not reported throughout the study. Further, in both combination studies, it is unclear if these effects are due to L-citrulline, other supplement ingredients, or the combination.
• Heart failure. Small clinical studies suggest that oral L-citrulline might be beneficial in patients with heart failure. Details: A very small clinical study in patients with heart failure with preserved ejection fraction (HFpEF) shows that taking L-citrulline malate 3 grams daily for 2 months decreases systolic pulmonary arterial pressure by 16% and improves the right ventricular ejection fraction after a stress test by 27% when compared to baseline (94962). The validity of this finding is limited by the lack of a control group. Another small open-label clinical study in patients with heart failure with reduced ejection fraction (HFrEF) shows that taking L-citrulline 3 grams daily for 4 months increases left ventricular ejection fraction by about 20% at rest and 13% during the stress test, and increases the right ventricular ejection fraction by about 15%, both at rest and with the stress test, when compared with no supplementation. This improved the heart failure functional class in 35% of patients (94955).
• Hypertension. It is unclear if oral L-citrulline is beneficial for lowering blood pressure. Details: A small clinical trial in adults with prehypertension shows that taking L-citrulline 2 grams with grape and cranberry polyphenols 548 mg daily for 6 weeks does not reduce mean ambulatory blood pressure when compared with a cellulose placebo (105969). A small crossover study in postmenopausal females with hypertension shows that taking L-citrulline 6 grams as a single dose does not improve systolic or diastolic blood pressure at rest or during 5 minutes of plantar flexion exercise when compared with placebo (110147). The effects of using L-citrulline regularly or in other patients with diagnosed hypertension is unclear.
• Lysinuric protein intolerance. Although there is interest in using oral L-citrulline for lysinuric protein intolerance, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Muscle strength. It is unclear if oral L-citrulline can improve muscle strength when used in conjunction with resistance training. Details: A clinical study in healthy resistance-trained adults shows that taking L-citrulline malate 2 grams daily for 8 weeks in conjunction with resistance training does not further increase lean mass or muscle strength, measured by leg and bench presses, when compared with a cellulose placebo and resistance training (97394).
• Muscular dystrophy. It is unclear if oral L-citrulline is beneficial in patients with Duchenne muscular dystrophy. Details: A small clinical study in adults with Becker muscular dystrophy, a milder form of Duchenne muscular dystrophy (DMD), shows that taking L-citrulline 5 grams with or without metformin 500 mg three times daily for 6 weeks improves 6-minute walking distance and decreases markers of muscle necrosis when compared to baseline (100975). A small clinical study in males aged 6.5-10 years with DMD shows that taking L-citrulline 2.5 grams with metformin 250 mg three times daily for 26 weeks does not appear to slow decline in motor function when compared with placebo. However, this combination seems to slow decline in children with more stable disease, defined as those who can walk at least 350 meters in 6 minutes (100976). The reasons for these disparate results are unclear, but they may be due to the different patient populations, disease severities, doses, and durations of therapy being studied.
• Postoperative pulmonary hypertension. It is unclear if oral citrulline prevents postoperative hypertension in children undergoing heart surgery. Details: A small clinical study in children 6 years of age and younger undergoing congenital heart surgery shows that higher blood levels of L-citrulline might protect against the incidence of postoperative hypertension. L-citrulline blood levels of at least 37 micromol/L immediately after surgery, and at 12, 24, and 36 hours postoperatively, protects against its development. However, supplementation with 1.9 grams/m2 during induction of anesthesia is not necessarily protective (16467).
• Post-polio syndrome. It is unclear if oral L-citrulline is beneficial for patients with this condition. Details: A small clinical study in adults with post-polio syndrome shows that taking L-citrulline 5 grams three times daily for 24 weeks does not improve 6-minute walking distance, motor function scores, muscle strength, or quality of life when compared with placebo (110149).
• Pulmonary hypertension. It is unclear if oral L-citrulline is beneficial in patients with pulmonary hypertension. Details: A very small clinical study in patients with idiopathic arterial pulmonary hypertension or pulmonary hypertension due to Eisenmenger syndrome shows that taking L-citrulline malate 1 gram three times daily for 2 weeks increases 6-minute walking distance by 44 meters and reduces mean pulmonary arterial pressure by 5% when compared with baseline (94963). The validity of these findings is limited by the small study size and the lack of a comparator group.
• Reye syndrome. Although there is interest in using oral L-citrulline for Reye syndrome, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Sickle cell disease. It is unclear if oral L-citrulline is beneficial in patients with sickle cell disease. Details: A small clinical study in children ages 10-18 years shows that taking L-citrulline 90-130 mg/kg daily in 2 divided doses for up to 9 months might reduce neutrophilia and other symptoms when compared with baseline (16463). The validity of these findings is limited by the small study size and the lack of a comparator group. More evidence is needed to rate L-citrulline for these uses.

(Read more about L-CITRULLINE)

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.

(Read more about SODIUM)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Fenugreek has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when the seed is used orally in medicinal amounts. Fenugreek seed powder 5-10 grams daily has been used with apparent safety for up to 3 years. Fenugreek seed extract 1 gram daily has been used with apparent safety for up to 3 months (7389,9783,18359,18362,49868,90112,90113,90117,93419,93420)(93421,93422,93423,96065,103285,108704).

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of fenugreek when used in larger amounts. Unusual body and urine odor has been reported after consumption of fenugreek tea. Although the odor appears to be harmless, it may be misdiagnosed as maple syrup urine disease (9782,96068).

PREGNANCY: LIKELY UNSAFE
when used orally in amounts greater than those found in food. Fenugreek has potential oxytoxic and uterine stimulant activity (12531). There are case reports of congenital malformations, including hydrocephalus, anencephaly, cleft palate, and spina bifida, after consumption of fenugreek seeds during pregnancy (96068). Consumption of fenugreek immediately prior to delivery may cause the neonate to have unusual body odor. Although this does not appear to cause long-term sequelae, it may be misdiagnosed as maple syrup urine disease (9781,96068).

LACTATION: POSSIBLY SAFE
when used orally to stimulate lactation, short-term. Although most available clinical studies lack safety testing in the lactating parent or infant (12535,22569,22570), some evidence suggests that taking fenugreek 1725 mg three times daily orally for 21 days does not cause negative side effects in the infant (90115).

(Read more about FENUGREEK)

POSSIBLY SAFE ...when used orally and appropriately. In clinical trials, L-citrulline has been used with apparent safety for up to 2 months at doses of 1.5-6 grams daily (94954,94956,94961,94962,100974). Doses of up to 15 grams have also been used as single doses or within a 24 hour period (16470,16473).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. L-citrulline has been used with apparent safety in infants at a dose of 0.17 grams/kg daily (16472). It has also been used in children 6.5-10 years of age at a dose of 7.5 grams daily for 26 weeks (100976). ...when used intravenously and appropriately. An intravenous bolus dose of L-citrulline 150 mg/kg followed by 9 mg/kg/hour for 48 hours has been used safely in children under 6 years of age (16469).

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

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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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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, fenugreek might have additive effects when used with anticoagulant or antiplatelet drugs.  Details Some of the constituents in fenugreek have antiplatelet effects in animal and in vitro research. However, common fenugreek products might not contain sufficient concentrations of these constituents for clinical effects. A clinical study in patients with coronary artery disease or diabetes shows that taking fenugreek seed powder 2.5 grams twice daily for 3 months does not affect platelet aggregation, fibrinolytic activity, or fibrinogen levels (5191,7389,49643).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fenugreek seed might have additive hypoglycemic effects when used with antidiabetes drugs.  Details Clinical research shows that fenugreek seed can reduce fasting blood glucose and 2-hour postprandial glucose levels in adults with type 2 diabetes (10284,90112,96065,105016).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek seed might alter the clinical effects of clopidogrel by inhibiting its conversion to the active form.  Details Animal research shows that fenugreek seed 200 mg/kg daily for 14 days increases the maximum serum concentration of clopidogrel by 21%. It is unclear how this affects the pharmacokinetics of the active metabolite of clopidogrel; however, this study found that concomitant use of fenugreek seed and clopidogrel prolonged bleeding time by an additional 11% (108701).

METOPROLOL (Toprol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fenugreek seed might have additive hypotensive effects when used with metoprolol.  Details Animal research shows that fenugreek seed 300 mg/kg daily for 2 weeks decreases systolic and diastolic blood pressure by 9% and 11%, respectively, when administered alone, and by 15% and 22%, respectively, when given with metoprolol 10 mg/kg (108703).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek might decrease plasma levels of phenytoin.  Details Animal research shows that taking fenugreek seeds for 1 week decreases maximum concentrations and the area under the curve of a single dose of phenytoin by 44% and 72%, respectively. This seems to be related to increased clearance (110905). So far, this interaction has not been reported in humans.

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of sildenafil and fenugreek might reduce levels and therapeutic effects of sildenafil.  Details Animal research shows that taking fenugreek seeds for 1 week reduces maximum concentrations and the area under the curve of a single dose of sildenafil by 27% and 48%, respectively (110898). So far, this interaction has not been reported in humans.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek may reduce the levels and clinical effects of theophylline.  Details Animal research shows that fenugreek 50 grams daily for 7 days reduces the maximum serum concentration (Cmax) of theophylline by 28% and the area under the plasma drug concentration-time curve (AUC) by 22% (90118).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek might have additive effects with warfarin and increase the international normalized ratio (INR).  Details Some fenugreek constituents have antiplatelet effects, although these might not be present in concentrations that are clinically significant (7389). In one case report, a patient taking warfarin experienced an increased INR when starting to take fenugreek in combination with boldo (5191).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of L-citrulline with antihypertensive drugs might have additive effects and increase the chance of hypotension.  Details L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). However, a meta-analysis of 5 small clinical studies suggests that taking L-citrulline 3-6 grams daily for 1-8 weeks does not lower blood pressure when compared with control (100974).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of phosphodiesterase-5 (PDE-5) inhibitors and L-citrulline might result in additive vasodilation.  Details L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). Theoretically, taking L-arginine with PDE-5 inhibitors might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).

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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, fenugreek seed is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, diarrhea, dyspepsia, flatulence, hypoglycemia, and nausea.
Serious Adverse Effects (Rare):
All ROA: Severe allergic reactions including angioedema, bronchospasm, and shock.

Endocrine ...Orally, large doses of fenugreek seed, 100 grams daily of defatted powder, have caused hypoglycemia (164,96068).

Gastrointestinal ...Orally, fenugreek seed can cause mild gastrointestinal symptoms, such as diarrhea, dyspepsia, abdominal distention and pain, nausea, and flatulence, especially when taken on an empty stomach (622,12534,18349,93421,96065,96068,105016).

Immunologic ...Fenugreek can cause allergic reactions when used orally and topically, and when the powder is inhaled (719,96068). Orally, fenugreek has caused bronchospasm, diarrhea, and itching, and skin reactions severe enough to require intravenous human immunoglobulin (96068). Topically, fenugreek paste has resulted in facial swelling, wheezing, and numbness around the head (719,96068). When used both orally and topically by a single individual, asthma and rhinitis occurred (96068). Inhalation of fenugreek powder has resulted in fainting, sneezing, runny nose, and eye tearing (719,96068).

Neurologic/CNS ...Orally, loss of consciousness has occurred in a 5 week-old infant drinking tea made from fenugreek (9782). Dizziness and headaches have been reported in clinical research of fenugreek extract (49551,93419). However, these events are rare.

Renal ...Orally, fenugreek aqueous see extract may increase the frequency of micturition, although this even appears to be rare (49551).

Other ...Consumption of fenugreek during pregnancy, immediately prior to delivery, may cause the neonate to have an unusual body odor, which may be confused with maple syrup urine disease. It does not appear to cause long-term sequelae (9781). This unusual body odor may also occur in children drinking fenugreek tea. A case of a specific urine and sweat smell following oral fenugreek extract use has been reported for a patient in one clinical trial (18349).
In 2011, outbreaks of enteroaggregative hemorrhagic Escherichia coli (EATEC) O104:H4 infection occurred in Germany and Spain. Epidemiological studies linked the outbreaks to fenugreek seeds that had been imported from Africa. However, laboratory analyses were unable to isolate the causative strain of bacteria from fenugreek seed samples (49776,49777,49781,90114).

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General ...Orally, L-citrulline seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, heartburn.

Gastrointestinal ...Orally, gastrointestinal intolerance, stomach discomfort, and heartburn have been reported with L-citrulline use (94955,94963,94966).

Genitourinary ...Orally, 2 of 25 patients with pulmonary hypertension reported increased urinary frequency and edema while taking 1 gram of powdered L-citrulline in water daily (94963).

Pulmonary/Respiratory ...Orally, 2 of 25 patients with pulmonary hypertension reported cough while taking 1 gram of powdered L-citrulline in water daily (94963).

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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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