Men's [Discontinued] by GNC Ultra Mega Green

POSSIBLY EFFECTIVE

• Diabetic neuropathy. Oral or intravenous alpha-lipoic acid 600-1800 mg daily seems to improve symptoms of peripheral neuropathy in patients with diabetes. Its benefits in patients with cardiac autonomic neuropathy are unclear. Details: Several clinical studies show that taking alpha-lipoic acid, either alone or in combination with gamma-lipoic acid, superoxide dismutase, or vitamin B12, seems to improve neuropathic sensory symptoms such as burning, pain, numbness, and prickling of the feet and legs, as well as objective measures such as ratings of neurological deficit and disability. Symptom improvement seems to occur within 3 to 5 weeks of oral or intravenous dosing (3540,3541,3557,3868,10148,12106,20473,20475,20478,20480)(20481,20484,20488,90447,103333,111429,111703). A meta-analysis of 10 clinical studies in adults with diabetic polyneuropathy shows that taking alpha-lipoic acid 600-1800 mg daily for 3 weeks to 2 years reduces the incidence, severity, and frequency of sensory symptoms and improves measures of impairment and neurological disability but does not improve vibration perception threshold or measures of nerve conduction when compared with placebo (111703). However, another meta-analysis of 6 studies in patients with type 1 or 2 diabetes, that includes some of the same studies, shows that giving alpha-lipoic acid 600-1800 mg daily orally or intravenously for 3-8 weeks does not improve neuropathic pain when compared with placebo (112937). Orally, alpha-lipoic acid 600-1800 mg daily in one to three divided doses has been used (3540,3541,3868,20475,20478,103333,111429). A specific combination product containing alpha-lipoic acid 600 mg and superoxide dismutase 140 IU (ALA600 SOD, Alfa Wassermann) has also been used (20488). Intravenously, alpha-lipoic acid 600 mg and 1200 mg daily have been used (3540,3541,3557,10148,20480,20481,20484). In one study, a specific product (Thiotacid, Eva Pharma) was used (103333). However, some preliminary clinical research shows that lower doses of alpha-lipoic acid are ineffective for improving nerve conduction velocity or subjective complaints of neuropathy (3869,20479,20482,20486,20487). Also, although there is some preliminary evidence that taking alpha-lipoic acid improves nerve function indices, such as Valsalva maneuver, Ewing's tests, or electrocardiogram measurements in patients with a specific type of diabetic neuropathy called cardiac autonomic neuropathy, taking alpha-lipoic acid orally does not improve clinical symptoms (3542,20483,20485,96223,107892).
• Hyperlipidemia. Oral alpha-lipoic acid seems to reduce levels of total and low-density lipoprotein (LDL) cholesterol in certain populations. However, it is unclear whether alpha-lipoic acid is clinically beneficial in patients with hyperlipidemia. Details: A meta-analysis of 11 clinical trials shows that taking alpha-lipoic acid 300-1200 mg daily for up to 16 weeks decreases total cholesterol by 10 mg/dL and LDL cholesterol by 9 mg/dL, but does not seem to improve high-density lipoprotein (HDL) cholesterol or triglycerides, when compared with placebo (100709). In addition, in a large group of generally healthy adults, taking alpha-lipoic acid 800-1200 mg for 4 years reduces levels of total and LDL cholesterol, as well as triglycerides, when compared with baseline. The 1200 mg daily dose was more effective than the 400 mg daily dose (104650). A meta-analysis of clinical research in various patient populations shows that taking oral alpha-lipoic acid 300-1200 mg daily for 2-16 weeks decreases levels of total cholesterol by 11 mg/dL, LDL cholesterol by 11 mg/dL, and triglycerides by 31 md/dL when compared with placebo. It is unclear whether dose or treatment duration affect these outcomes (107885). These findings are limited by the high heterogeneity of the included studies and patient populations. One clinical study in adults with gestational diabetes, most of whom had elevated cholesterol levels at baseline, shows that taking oral alpha-lipoic acid (Puritan's Pride) 100 mg daily for 8 weeks reduces triglycerides, but does not improve levels of total, HDL, or LDL cholesterol, when compared with placebo (107890). The validity of this study is limited due to short duration of treatment. While many patients in these studies had elevated lipid levels at baseline, none of the studies specifically evaluated patients with hyperlipidemia. Thus, the benefits of alpha-lipoic acid in these patients is unclear.
• Obesity. Most research shows that oral alpha-lipoic acid seems to improve weight loss by a small amount. Details: While individual clinical studies show mixed results (21674,97630,100710,103327,103334), meta-analyses of clinical research show that taking alpha-lipoic acid 300-1800 mg daily for 2-48 weeks can modestly reduce body weight by 0.7-2.3 kg and body mass index (BMI) by up to 0.5 kg/m2 when compared with placebo in overweight individuals or patients with obesity. The magnitude of these improvements are not dependent on the dose or duration of treatment (96231,96232,103332,111294). While these improvements are statistically significant, they may not be clinically meaningful. In addition, a network meta-analysis of randomized controlled trials in adults with obesity shows that taking alpha-lipoic acid 300-600 mg orally daily for 8-10 weeks improves some markers of insulin resistance, but not blood pressure or cholesterol levels (111294). Taking alpha-lipoic acid might also reduce body weight in overweight children or children with obesity. In adolescents aged 10-17 years, clinical research shows that taking alpha-lipoic acid 300 mg twice daily for 3 months reduces body weight by 3.2 kg when compared with placebo. However, there was no effect on blood lipids or fasting blood glucose (103330). Also, a small clinical study in children 8-16 years of age shows that taking alpha-lipoic acid (Tiobec 800, Laborest) 800 mg daily for 12 weeks does not improve body weight, BMI, blood pressure, blood lipids, glycemic control, insulin resistance, or endothelial function when compared with placebo (100708). However, this study may have been inadequately powered to detect a difference in many of these outcomes.

POSSIBLY INEFFECTIVE

• Alcohol-related liver disease. Oral alpha-lipoic acid does not seem to improve liver function in patients with alcohol-related liver disease. Details: Taking alpha-lipoic acid orally 300 mg daily for up to 6 months does not appear to improve liver function or reduce liver damage when compared with placebo in patients with alcohol-related liver disease (3880,21678).
• Altitude sickness. Oral alpha-lipoic acid, in combination with vitamins C and E, does not seem to be beneficial for altitude sickness prevention or treatment. Details: Clinical research in healthy volunteers ascending to 5200 meters shows that taking alpha-lipoic acid 600 mg in combination with vitamin C 1 gram and vitamin E (alpha-tocopherol) 400 IU in four divided doses daily, beginning on the day of travel to high altitude and continuing for 2 weeks thereafter, does not prevent the occurrence nor decrease the severity of altitude sickness when compared with placebo (20499).
• Contrast induced nephropathy. Oral alpha-lipoic acid does not seem to prevent nephropathy after undergoing coronary angiography. Details: In diabetic patients at low risk for contrast induced nephropathy, alpha-lipoic acid (Thioactacid 600 mg RH, MEDA Manufacturing GmbH) 600 mg taken 30 minutes prior to and 24 and 48 hours after undergoing coronary angiography, with or without standard hydration therapy, does not reduce the risk of contrast induced nephropathy when compared with standard hydration therapy (90442). In addition, treatment with alpha-lipoic acid 600 mg orally every 8 hours beginning the afternoon prior to angiography and continuing for 2 days does not attenuate the maximum increase in serum creatinine or reduce the incidence of contrast induced nephropathy in most patients when compared with standard hydration therapy alone (90446).
• Diabetes. Oral or intravenous alpha-lipoic acid does not seem to be beneficial for glycemic control in patients with type 2 diabetes. Details: Although some conflicting findings from individual studies exist, the overall evidence does not support the use of oral or intravenous alpha-lipoic acid for improving glycemic control or insulin sensitivity in patients with type 2 diabetes (3545,3874,3875,3876,20490,20493,20494,20495,20496,90443)(90445,110118,111305). A meta-analysis of 16 small clinical studies in patients with type 2 diabetes shows that taking alpha-lipoic acid 200-1200 mg daily for up to 52 weeks leads to slight improvements in glycemic control and body weight, but these improvements are not clinically significant. When compared with placebo, alpha-lipoic acid reduced fasting blood glucose by 6 mg/dL, glycated hemoglobin (HbA1c) by 0.17%, body weight by 0.7 kg, and body mass index (BMI) by 1.1 kg/m2. While triglyceride levels were reduced by 19 mg/dL, improvements in other lipids levels and blood pressure were lacking (110118). A specific alpha-lipoic acid product administered orally or intravenously in some of these studies was Thioctacid (Asta Medica) (3874,3875,3876). Alpha-lipoic acid has also been evaluated in patients with gestational diabetes or type 1 diabetes. A small clinical study in adults with gestational diabetes shows the taking alpha-lipoic acid (Puritan's Pride) 100 mg daily for 8 weeks improves fasting blood glucose levels and insulin sensitivity but does not affect HbA1C when compared with placebo (107890). The validity of this study is limited due to its short duration, which was likely inadequate to detect a change in HbA1c. Also, one small clinical study in adolescent patients with type 1 diabetes who show signs of early stage diabetic cardiomyopathy shows that taking alpha-lipoic acid 300 mg twice daily for 4 months, in combination with insulin therapy, improves left ventricular systolic and diastolic function (90443).
• Diabetic retinopathy. Oral alpha-lipoic acid does not seem to prevent macular edema in patients with diabetic retinopathy. Details: Some research shows that taking oral alpha-lipoic acid 600 mg daily for 24 months does not improve the incidence of clinically significant macular edema when compared with placebo in patients with mild to moderate nonproliferative diabetic retinopathy (20491).
• HIV/AIDS-related dementia. Oral alpha-lipoic acid does not seem to improve cognitive impairment related to this condition. Details: Clinical research shows that taking alpha-lipoic acid 600 mg daily, alone or along with selegiline (Deprenyl), for 10 weeks may worsen HIV-associated cognitive impairment and does not affect mood or functional status when compared with placebo in patients with confirmed HIV infection and evidence of cognitive impairment (1556).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral alpha-lipoic acid is beneficial for age-related cognitive decline. Details: Preliminary clinical research in elderly adults shows that taking alpha-lipoic acid 600 mg orally daily for 12 weeks does not improve cognitive function scores when compared with baseline (111303). The validity of this study is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). It is unclear if oral alpha-lipoic acid is beneficial for AMD. Details: A small clinical trial shows that taking alpha-lipoic acid (Pure Encapsulations) 1200 mg daily for 18 months does not improve visual acuity or reduce the rate of atrophy when compared with placebo in patients with advanced AMD (103335). It is unclear if alpha-lipoic acid would be beneficial in patients with less severe symptoms of AMD.
• Age-related testosterone deficiency. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing alpha-lipoic acid 800 mg, myo-inositol, folic acid, and apple (Sinopol Forte, Laborest) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these findings is limited by the small sample size and lack of a comparator group, and it is unclear if these effects are due to alpha-lipoic acid, other ingredients, or the combination.
• Aging skin. Topical alpha-lipoic acid may be beneficial for aging skin. Details: A small clinical study shows that applying a cream containing alpha-lipoic acid 5% to the face twice daily for 12 weeks reduces the fine lines and roughness associated with aging of facial skin when compared with a control cream (12021).
• Alzheimer disease. It is unclear if oral alpha-lipoic acid is beneficial for this condition. Details: Some preliminary clinical research shows that taking alpha-lipoic acid 600 mg once daily in combination with standard cholinesterase inhibitors may slow cognitive decline when compared with cholinesterase inhibitors alone in some patients with Alzheimer disease (20500,90437). However, higher-quality clinical research shows that taking alpha-lipoic acid 600-900 mg daily for up to 2 years, in combination with vitamin C and vitamin E, does not affect cognitive function when compared with placebo in patients with mild to moderate Alzheimer disease (19206,20501).
• Amanita mushroom poisoning. Evidence on the use of intravenous alpha-lipoic acid for amanita mushroom poisoning is limited to anecdotal reports. Details: Intravenous alpha-lipoic acid has been used in combination with other treatments for poisoning from amanita mushroom ingestion. Its use is controversial. Reports are anecdotal, and experimental evidence does not support its effectiveness. Some researchers recommend against its use (105,1548,1549,3871,3879).
• Anthracycline cardiotoxicity. It is unclear if oral alpha-lipoic acid is effective for the prevention of anthracycline cardiotoxicity. Details: A small clinical study in patients with breast cancer receiving doxorubicin shows that taking alpha-lipoic acid 600 mg daily for 6 months does not improve ejection fraction but does decrease levels of brain natriuretic peptide (BNP), a marker of ventricular hypertrophy, when compared with placebo (110112).
• Antipsychotic-induced hyperprolactinemia. It is unclear if oral alpha-lipoic acid is effective for the prevention or treatment of antipsychotic-induced hyperprolactinemia. Details: A very small, open-label study in patients with schizophrenia shows that taking alpha-lipoic acid 600 mg daily along with conventional antipsychotic therapy for 12 weeks reduces prolactin levels by 51% when compared to baseline (110116). The validity of this finding is limited by the lack of a control group.
• Antipsychotic-induced metabolic side effects. Small clinical studies suggest that oral alpha-lipoic acid does not seem to improve antipsychotic-induced metabolic side effects in patients with schizophrenia. Details: A very small, open-label study in patients with schizophrenia shows that taking alpha-lipoic acid 600 mg daily along with conventional antipsychotic therapy for 12 weeks reduces fasting blood glucose levels by around 17 mg/dL but actually increases glycated hemoglobin (HbA1c) by 0.14% when compared to baseline. No improvements in body weight or lipid levels were reported (110116). Another small clinical study in patients with schizophrenia stabilized on antipsychotic therapy for at least 1 year shows that taking alpha-lipoic acid 100 mg daily for 16 weeks does not improve body mass index (BMI) when compared with placebo (110115).
• Aromatase inhibitor-induced arthralgia. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with estrogen receptor positive (ER+) breast cancer and aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, Gamfarma Srl) containing alpha-lipoic acid 240 mg, Boswellia serrata 40 mg, methylsulfonylmethane 200 mg, and bromelain 20 mg once daily for 6 months reduces arthralgia intensity when compared to baseline, with around 22% of patients having complete symptom resolution at the end of the study (109570). The validity of these findings is limited by the lack of a control group.
• Atrial fibrillation. It is unclear if oral alpha-lipoic acid is beneficial for atrial fibrillation. Details: Clinical research shows that taking alpha-lipoic acid 600 mg daily for 12 months does not reduce the recurrence of atrial fibrillation when compared with placebo in patients who underwent a catheter ablation procedure. However, there was a decrease in the need for antiarrhythmic drugs in patients receiving alpha-lipoic acid (97628).
• Back pain. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in adults with chronic lower back pain and sciatica suggests that taking a combination of alpha-lipoic acid 800 mg, palmitoylethanolamide 600 mg, and myrrh 200 mg daily for 30 days, along with periradicular infiltrations of oxygen-ozone, is associated with resolution of pain in 17% more patients when compared with periradicular steroid infiltrations at 60 days (111308). However, it is unclear if this effect is due to alpha-lipoic acid, other ingredients, or the combination.
• Beta-thalassemia. It is unclear if oral alpha-lipoic acid is beneficial for reducing iron accumulation in beta-thalassemia major. Details: A small, crossover study in patients with beta-thalassemia major who are receiving iron chelation therapy shows that adding oral alpha-lipoic acid 600 mg before breakfast or dinner for 8 weeks reduces levels of serum ferritin when compared with placebo (107888). Serum ferritin was reduced by 104 ng/mL and 38 ng/mL in the treatment and placebo groups, respectively. The validity of this finding is limited due to the small, exploratory nature of the study.
• Bipolar disorder. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking acetyl-L-carnitine 1000 mg plus alpha-lipoic acid 600 mg up to three times daily for 12 weeks does not improve depression when compared with placebo in patients with type I or type II bipolar disorder (90441).
• Burning mouth syndrome. It is unclear if oral alpha-lipoic acid is beneficial for burning mouth syndrome. Details: A meta-analysis of nine small, low-quality clinical trials in patients with burning mouth syndrome shows that taking alpha-lipoic acid 400-800 mg daily for up to 2 months does not reduce pain intensity when compared with placebo or active controls such as multivitamins, Biotene mouth rinse, capsaicin, laser therapy, clonazepam, or pregabalin. However, in an analysis of three placebo-controlled studies, alpha-lipoic acid increased the likelihood of any burning mouth syndrome-related symptom improvement by 92% when compared with placebo (110111). Individual studies, most of which were included in the analysis, show conflicting results overall (20474,21661,21662,21663,21664,21665,21666,111427). One small clinical trial shows that taking alpha-lipoic acid 600 mg daily improves symptoms of burning mouth syndrome in patients who had never previously been treated with anxiolytics or antidepressants, but not in those who had received these prior treatments (21668). This suggests that alpha-lipoic acid may improve symptoms of burning mouth syndrome resulting from stress, but not from depression or drug-induced hyposalivation.
• Cancer. Although there is interest in using oral alpha-lipoic acid for preventing or treating cancer, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Cardiovascular disease (CVD). Although there is interest in using oral alpha-lipoic acid for preventing or treating CVD, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Carpal tunnel syndrome. It is unclear if oral alpha-lipoic acid is beneficial for carpal tunnel syndrome, either before or after surgery. Details: In patients with mild to moderate carpal tunnel syndrome, preliminary clinical research shows that taking alpha-lipoic acid 600 mg daily for 60 days reduces pain by a moderate amount when compared with not taking alpha-lipoic acid, but with no effect on functionality (103328). In patients with neuropathic pain due to carpal tunnel syndrome, giving alpha-lipoic acid 600 mg intravenously daily for 30 days, then 600 mg orally daily for 60 days, decreases pain on a visual analog scale, and improves functionality when compared with oral alpha-lipoic acid alone, or no treatment (112938). Alpha-lipoic acid has also been studied in combination with other ingredients. One study shows that taking a combination of alpha-lipoic acid 600 mg and gamma-linolenic acid 360 mg for 90 days improves functional scores and subjective symptom scores when compared to baseline (21653). The validity of this finding is limited by the lack of a comparator group. Another clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, B6, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to alpha-lipoic acid, other ingredients, or the combination. Alpha-lipoic acid has also been evaluated in patients who have undergone carpal tunnel release surgery. Taking alpha-lipoic acid 600 mg daily for 40 days starting immediately after surgery does not improve the rate of nerve recovery when compared with placebo, although it seems to reduce the occurrence of post-operative pillar pain, which is a common complication of carpal tunnel release surgery (96233).
• Cataracts. Although there is interest in using oral alpha-lipoic acid for cataracts, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Cervical dysplasia. It is unclear if oral alpha-lipoic acid is beneficial in patients with cervical dysplasia. Details: A small clinical study in patients with low-grade cervical intraepithelial neoplasia shows that taking alpha-lipoic acid 600 mg daily for 3 months reduces the proportion of patients with intraepithelial neoplasia by 95% when compared with placebo (110113).
• Chemotherapy-induced peripheral neuropathy. There is conflicting evidence regarding the effectiveness of oral alpha-lipoic acid for the prevention of chemotherapy-induced peripheral neuropathy. Details: One clinical study shows that taking alpha-lipoic acid 600 mg three times daily for 24 weeks during treatment with cisplatin or oxaliplatin does not affect the symptoms or severity of chemotherapy-induced peripheral neuropathy when compared with placebo (90439). However, another small clinical study in patients with breast cancer receiving paclitaxel shows that taking alpha-lipoic acid 600 mg daily for 6 months reduces the severity of peripheral neuropathy when compared with placebo (110112). The reason for this disparate finding is unclear, but it may be due to differences in chemotherapy regimens. Alpha-lipoic acid has also been evaluated in combination with other ingredients. A small clinical study shows that taking a specific product (Opera, Gamfarma s.r.l.) containing alpha-lipoic acid 240 mg, methylsulfonylmethane (MSM) 200 mg, Boswellia serrata 40 mg, and bromelain 20 mg daily for 12 weeks reduces overall pain when compared to baseline in adults with chemotherapy-induced peripheral neuropathy (96449). The validity of these findings is limited by the lack of a control group. Other preliminary clinical research shows that taking alpha-lipoic acid 600 mg orally once daily and ipidacrine 20 mg orally three times daily throughout 6 paclitaxel-based chemotherapy cycles improves sensory nerve action potential parameters when compared with control (111292). It is unclear if these effects are due to alpha-lipoic acid, the other ingredients, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral alpha-lipoic acid for CFS, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Chronic kidney disease (CKD). It is unclear if oral alpha-lipoic acid is beneficial for CKD. Details: Preliminary clinical research in patients with stage 2 or 3 CKD related to autosomal dominant polycystic kidney disease shows that taking alpha-lipoic acid 1.6 grams daily for 6 months has modest benefits on biochemical markers and cognitive tests when compared to control. Taking alpha-lipoic acid reduces serum glucose, insulin, C-reactive protein (CRP), and uric acid levels, and improves insulin resistance and flow-mediated dilation and cognitive test results. However, there was no effect on intima media thickness or the ankle brachial index (101867).
• Coronary artery bypass graft (CABG) surgery. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients undergoing elective CABG surgery shows that taking a combination of alpha-lipoic acid 100 mg, coenzyme Q10 100 mg, magnesium orotate 400 mg, and omega-3 fatty acids 300 mg three times daily, with selenium 200 mcg once daily, for up to 2 months prior and 1 month after surgery, decreases plasma troponin levels and reduces the average postoperative hospital stay by 1.2 days when compared with placebo (21651). It is unclear if this effect is due to alpha-lipoic acid, the other ingredients, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral alpha-lipoic acid is beneficial in patients with persistent loss of the sense of smell after COVID-19 infection. Details: In adults with sense of smell loss persisting for more than 3 months after COVID-19 infection, adding alpha-lipoic acid 300 mg twice daily orally for 12 weeks to olfactory training reduces the incidence of anosmia, and improves the olfactory threshold, the sense of smell measured on a visual analog scale, and the smell identification score by a similar amount to placebo (112935).
• Diabetic nephropathy. When used in combination with certain conventional medications, intravenous or oral alpha-lipoic acid may improve some measures of albuminuria in patients with diabetic nephropathy. Details: Preliminary clinical research shows that intravenous alpha-lipoic acid (YantaiZhichu Pharmaceutical Co., Ltd.) 450 mg plus intravenous alprostadil 20 mcg once daily for 14 days reduces urinary albumin excretion rate by 23% and cystatin C levels by 19% when compared with alprostadil alone (96221). Patients treated with alpha-lipoic acid 600 mg intravenously plus valsartan 80 mg orally once daily for 14 days showed a 25% lower urinary albumin excretion rate and a 27% and 31% lower serum level of beta2-microglobulin and cystatin C, respectively, when compared with patients treated with valsartan alone (101866). A meta-analysis of clinical research in adults with diabetic nephropathy shows that taking oral alpha-lipoic acid 300 mg, 450 mg, or 600 mg daily in combination with oral valsartan 80 mg daily for 14 days reduces urinary albumin excretion rate, as well as levels of urinary albumin and serum beta 2-microglobulin, when compared with either valsartan or alpha-lipoic acid alone (107891). These findings are limited by the high heterogeneity of the included studies and the presence of potential publication bias. Additionally, the long-term benefits of alpha-lipoic acid are unclear. Another meta-analysis of clinical research in patients with diabetes shows that taking oral alpha-lipoic acid 600 mg daily in conjunction with other medications (e.g. antihypertensives, vitamin B6) for 3-18 months reduces levels of urine albumin, but does not improve urinary albumin excretion rate, when compared with placebo. Notably, alpha-lipoic acid alone did not affect outcomes (107886). The validity of these findings is limited by the high heterogeneity of the included studies; additionally, the quality of evidence was considered low to moderate.
• Dry eye. It is unclear if topical alpha-lipoic acid is beneficial in patients with dry eye. Details: A small clinical study in patients with diabetes and dry eye symptoms shows that application of an eye drop containing alpha-lipoic acid 0.1% and hydroxy-propyl-methylcellulose (HPMC) 0.3% three times daily for 2 months does not improve subjective or objective measures of dry eye symptoms when compared with HPMC alone (110119).
• Dysmenorrhea. It is unclear if oral alpha-lipoic acid is beneficial for dysmenorrhea. Details: Preliminary clinical research shows that taking alpha-lipoic acid 600 mg orally daily, with or without mefenamic acid 250 mg daily, for 5 days starting before menstruation reduces pain associated with moderate to severe primary dysmenorrhea by approximately 24% and 44%, respectively, when compared to baseline (101871). The validity of this finding is limited by the lack of a comparator group.
• Erectile dysfunction (ED). It is unclear if oral or intravenous alpha-lipoic acid is beneficial for ED. Details: Preliminary clinical research in males with diabetes and ED shows that intravenous alpha-lipoic acid 600 mg with alprostadil 10 mcg once daily for 14 days improves the quality and frequency of erection in 95% of patients, compared with only 81% of those taking tadalafil 5 mg orally daily (96224). It is not clear if this improvement is due to alpha-lipoic acid, alprostadil, or the combination. Another very small study in males with mild ED, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing alpha-lipoic acid 800 mg, myo-inositol, folic acid, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these finding is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to alpha-lipoic acid, other ingredients, or the combination.
• Fibromyalgia. It is unclear if intravenous alpha-lipoic acid is beneficial for fibromyalgia. Details: Preliminary clinical research shows that taking alpha-lipoic acid (SiSU Vita Health) 600-1800 mg daily for 4 weeks does not reduce pain intensity when compared with placebo in patients with fibromyalgia (104655). Alpha lipoic acid has also been studied as a combination therapy for fibromyalgia. Preliminary clinical research in adults with fibromyalgia shows that taking a combination of alpha-lipoic acid and pregabalin for 6 weeks does not improve pain or depression scores when compared with either product alone (111428). However, the study may have been inadequately powered to detect a difference between groups.
• Glaucoma. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with open-angle glaucoma shows that taking a combination product containing alpha-lipoic acid 100 mg, omega-3 fatty acids 2240 mg, vitamin C 180 mg, vitamin E 27.9 mg, lutein 10 mg, zeaxanthin 2 mg, zinc 15 mg, copper 1 mg, and taurine 150 mg (NuaDHA Vision, Nua Biological) orally daily for 6 months does not improve intraocular pressure when compared with baseline (111310).
• Heart failure. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with heart failure participating in a handgrip exercise shows that taking alpha-lipoic acid, vitamin E, and vitamin C reduces mean arterial pressure by about 6 mmHg and reduces vascular resistance by about 12% when compared with placebo (19219). The first dose consisted of vitamin E 200 IU, vitamin C 500 mg, and alpha-lipoic acid 300 mg. The subsequent dose consisted of vitamin E 400 IU, vitamin C 500 mg, and alpha-lipoic acid 300 mg (19219). It is unclear if these effects are due to alpha-lipoic acid, other ingredients, or the combination.
• Hemorrhoids. It is unclear if oral alpha-lipoic acid is beneficial for hemorrhoids. Details: A preliminary open-label clinical trial shows that taking alpha-lipoic acid 200 mg daily for 12 weeks decreases anal pain while sitting, pain at defecation, itching, and bleeding when compared with no treatment in patients with second- and third-degree hemorrhoids (100707). The validity of these results is limited by a lack of blinding and placebo control.
• Herniated disc. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in adults with acute lumbosacral radiculopathy secondary to lumbar disc herniation shows that taking a combination supplement containing alpha-lipoic acid 404 mg, myrrh, and palmitoylethanolamide (PEA) (Tiobec Dol, Uriach Italy Srl) twice daily for 4 weeks, along with steroids and as needed opioids, reduces pain and disability and improves physical but not mental health as it pertains to quality of life when compared with steroids and as needed opioids alone (111711). However, it is unclear if these effects are due to alpha-lipoic acid, other ingredients, or the combination.
• HIV/AIDS. It is unclear if oral alpha-lipoic acid is beneficial for patients with HIV/AIDS who are unresponsive to highly active antiretroviral therapy (HAART). Details: A small clinical study in patients who were unresponsive to HAART shows that taking alpha-lipoic acid (Alpha Lipoic Sustain 300, Jarrow Formulas) 300 mg three times daily for 6 months improves lymphocyte proliferation and whole blood glutathione levels when compared with placebo. However, there was no change in HIV RNA levels or CD4 count (21655).
• Hypertension. It is unclear if oral alpha-lipoic acid is beneficial for hypertension. Details: Clinical research in a small number of patients with mild (stage I) hypertension shows that adding alpha-lipoic acid 600 mg daily to quinapril 40 mg daily for 8 weeks does not significantly decrease blood pressure when compared with quinapril alone (21656). A meta-analysis of 11 clinical trials shows that alpha-lipoic acid lowers systolic blood pressure by a mean of about 5 mmHg, and diastolic blood pressure by a mean of about 3 mmHg, but there is significant heterogeneity between the studies. The small decrease in blood pressure is also only seen with doses of alpha-lipoic acid below 800 mg daily when given for 12 weeks or less (112934).
• Hypertriglyceridemia. Clinical studies suggest that oral alpha-lipoic acid does not reduce triglyceride levels in patients with hypertriglyceridemia, however it might be beneficial in certain populations. Details: In overweight adults with elevated triglycerides, taking alpha-lipoic acid 600 mg daily for 24 weeks does not reduce triglyceride levels when compared with placebo (103327). In addition, a meta-analysis of 11 clinical trials in patients with or without hypertriglyceridemia at baseline shows that taking alpha-lipoic acid 300-1200 mg daily for up to 16 weeks does not improve triglyceride levels when compared with placebo (100709). However, one clinical study in adults with gestational diabetes, most of whom had elevated triglyceride levels at baseline, shows that taking alpha-lipoic acid (Puritan's Pride) 100 mg daily for 8 weeks reduces triglyceride levels by 30 mg/dL, compared with an increase of 5 mg/dL in those taking placebo, a difference that was statistically significant (107890). The validity of this study is limited due to short duration of treatment.
• Impaired glucose tolerance (prediabetes). It is unclear if oral or intravenous alpha-lipoic acid is beneficial for prediabetes. Details: A small clinical study in patients with prediabetes shows that intravenous alpha-lipoic acid 600 mg daily for 2 weeks decreases postprandial plasma glucose, steady state plasma insulin, cholesterol, and fatty acid levels and increases insulin sensitivity when compared with placebo (21657). In a large group of generally healthy adults, taking alpha-lipoic acid 800-1200 mg for 4 years reduces levels of fasting plasma glucose when compared with baseline. The 1200 mg daily dose was more effective than the 400 mg daily dose (104650). While some patients in this study had prediabetes or impaired fasting glucose at baseline, the study did not specifically evaluate patients with prediabetes.
• Infertility. Although there is interest in using oral alpha-lipoic acid to increase the chance of pregnancy, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for infertility.
• Interstitial cystitis. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In individuals with vulval pain associated with painful bladder syndrome, clinical research shows that taking a specific product containing alpha-lipoic acid 600 mg, docosahexaenoic acid 250 mg, eicosapentaenoic acid 16.67 mg, vitamin E 12 mg, vitamin D 5 mg, and magnesium 56.25 mg (ALAnerv Age; Alfa Wassermann) daily in combination with amitriptyline up to 30 mg daily for 12 weeks reduces pelvic pain between 15% to 49% more than amitriptyline alone. Also, use of the combination supplement more than doubled the number of patients with an improvement in pain during intercourse (97629). It is unclear if the benefit is associated with alpha-lipoic acid, other ingredients, or the combination.
• Lyme disease. Although there is interest in using oral alpha-lipoic acid for Lyme disease, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Male infertility. Most small clinical studies suggest that oral alpha-lipoic acid might improve sperm characteristics in males with infertility. However, it is unclear whether alpha-lipoic acid improves pregnancy or live birth rates in these individuals. Details: A meta-analysis of three small clinical studies in males with infertility shows that taking alpha-lipoic acid 600 mg daily for 80-90 days improves sperm motility and increases sperm concentration and semen volume when compared with placebo (110108). More recent clinical trials in males with idiopathic asthenozoospermia or history of recurrent pregnancy loss shows that taking alpha-lipoic acid 600 mg orally daily for 80-90 days improves sperm motility, sperm concentration, and semen volume and reduces sperm DNA damage when compared with placebo (110110,111425). However, a small clinical study in males with infertility due to high levels of sperm DNA damage shows that taking alpha-lipoic acid 600 mg daily for 80 days does not improve pregnancy rate, sperm motility, sperm concentration, semen volume, or other measures of sperm health when compared with placebo (110109). Alpha-lipoic acid has also been evaluated in combination with other ingredients. A small clinical study in males with oligoasthenoteratozoospermia (OAT) shows that taking one tablet daily of a specific product (Fertiplus SOD, Idi-Pharma) containing alpha-lipoic acid, superoxide dismutase, glutathione, and other nutrients 30 days prior to IVF procedures improves the pregnancy rate from 9% of all embryo transfers pre-treatment to 45% and reduces the rate of miscarriage when compared to baseline (97627). It is unclear if the benefit is associated with alpha-lipoic acid, the other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral alpha-lipoic acid is beneficial in patients with metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking alpha-lipoic acid 600 mg orally daily for 12 weeks modestly improved serum triglyceride levels, but not serum low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo (111307). However, the study may have been inadequately powered to detect a difference between groups.
• Migraine headache. It is unclear if oral alpha-lipoic acid is beneficial in patients with migraine headaches. Details: A small clinical study in females with episodic migraines shows that taking alpha-lipoic acid 300 mg twice daily for 12 weeks reduces migraine frequency by around 2 attacks per month and improves migraine severity, but not the duration of migraine pain, when compared with placebo (110117). Another small clinical study in adults with migraines shows that taking alpha-lipoic acid 400 mg twice daily for 6 months reduces migraine frequency by at least 50% in 69% of patients and reduces the need for migraine treatment by 56% when compared to baseline, although the validity of these findings is limited by the lack of a control group (96229). In contrast, one small clinical study in adults with migraine headaches shows that taking alpha-lipoic acid 600 mg daily for 3 months does not improve monthly migraine attack frequency when compared with placebo (21660). The reasons for these disparate findings are unclear. Alpha-lipoic acid has also been evaluated in adolescents for migraine prophylaxis. A small open-label study in adolescents aged 10-19 years with a history of migraine shows that taking alpha-lipoic acid 300 mg with flunarizine 5 mg as prophylaxis daily for 12 weeks reduces the frequency of migraine attacks and reduces monthly migraine headache days by 9 days, but does not reduce migraine severity or measures of disability when compared with flunarizine alone. For every 3 patients treated with alpha-lipoic acid and flunarizine over flunarizine alone, 1 additional patient had a 50% or greater reduction in migraine frequency (111706). The validity of these effects is limited by a lack of blinding.
• Muscle strength. It is unclear if oral alpha-lipoic acid prevents a loss of muscle strength after exercise. Details: In athletes, a small clinical trial shows that taking a single dose of alpha-lipoic acid 150 mg (Athenion GmbH) after an intensive load protocol does not prevent loss of leg strength approximately 24 hours later when compared with placebo. However, taking the same dose for 2 days, followed by 300 mg daily during a 6-day training protocol, results in the maintenance of leg strength, compared with a loss in those taking placebo (104652).
• Neck pain. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of alpha-lipoic acid 600 mg plus superoxide dismutase 140 IU once daily for 2 months, along with physiotherapy, reduces chronic neck pain in approximately 50% more patients when compared with physiotherapy alone (90440).
• Neuropathic pain. It is unclear if oral alpha-lipoic acid is beneficial in patients with neuropathic pain. Details: In patients with peripheral neuropathies, taking alpha-lipoic acid orally, up to 1800 mg daily for 6 weeks, is less effective for reducing pain intensity scores and improving quality of life than pregabalin, taken orally in doses up to 450 mg daily (112940). A nonblinded clinical study in patients with refractory chronic lumbosacral radicular pain shows that taking alpha lipoic acid orally, 600 mg three times daily for 3 weeks followed by 600 mg daily for 2 weeks, in addition to a single, pulsed radiofrequency treatment to the dorsal ganglion, improves pain severity and disability scores at 6 months when compared with pulsed radiofrequency treatment alone. A pain score of less than 4 is achieved at 12 weeks in about 80% of patients taking alpha lipoic acid, compared with about 65% of patients without alpha-lipoic acid. (107895).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral alpha-lipoic acid is beneficial for NAFLD. Details: Small clinical studies in adults with NAFLD and obesity show that taking alpha-lipoic acid 600 mg orally twice daily for 8-12 weeks does not improve liver health markers, such as liver function test levels or liver steatosis, cholesterol levels, body weight, or visceral fat when compared with placebo or control (104660,100710,111304). However, these clinical trials show that taking alpha-lipoic acid 600 mg orally twice daily for 8-12 weeks may provide small improvements in interleukin-6 levels, adiponectin levels, and insulin resistance (104660,100710). However, these studies may have been inadequately powered to detect differences in some of these outcomes.
• Orthostatic hypotension. It is unclear if oral alpha-lipoic acid is beneficial for orthostatic hypotension. Details: Preliminary clinical research shows that taking alpha-lipoic acid 430-788 mg orally daily for a mean of 2.3 years attenuates changes in blood pressure upon standing when compared with baseline in some patients with chronic neurogenic orthostatic hypotension or orthostatic intolerance (101868).
• Pain (chronic). It is unclear if oral alpha-lipoic acid is beneficial for various chronic pain conditions. Details: A clinical study in patients with untreated, mild to moderate idiopathic pain (i.e. neuropathic pain, joint pain, and muscle pain with unknown etiology) shows that taking oral alpha-lipoic acid 400 mg once or twice daily for 2 months may improve pain severity when compared with baseline, with greater effects observed with daily doses of 800 mg (107887). Although the study enrolled a control group, a statistical comparison between groups was not conducted, limiting the validity of this finding. Additionally, sub-analyses evaluating outcomes based on type of chronic pain were not conducted.
• Periodontitis. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing alpha-lipoic acid 25 mg, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin C, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not reduce periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation, among others, when compared with placebo (111708).
• Peripheral arterial disease (PAD). It is unclear if oral alpha-lipoic acid is beneficial for PAD. Details: Preliminary clinical research shows that taking alpha-lipoic acid 300 mg twice daily reduces pain associated with exercise in people with PAD and claudication when compared with placebo. However, exercise tolerance does not seem to improve (16391).
• Polycystic ovary syndrome (PCOS). It is unclear if oral alpha-lipoic acid is beneficial for PCOS. Details: Alpha-lipoic acid has been studied alone and in combination with inositol for the treatment of PCOS. Observational research shows that taking alpha-lipoic acid 2000 mg, alone or in combination with myo-inositol (Sinopol, Laborest s.r.l.) 800-1000 mg, daily for 3-24 months is associated with reduced insulin levels and reduced menstrual cycle length, but not weight loss or improvements in hirsutism or insulin resistance, when compared with baseline (101869,101870). Another observational study shows that taking alpha lipoic acid 800 mg with a higher dose of myo-inositol 2000 mg is associated with slightly greater weight loss when compared with a lower dose of myo-inositol 1000 mg daily (103751). Also, taking alpha-lipoic acid 400 mg orally daily for 12 weeks does not affect levels of hormones, although improvements occur when alpha-lipoic acid is taken in combination with inositol 1000 mg daily (101870). The validity of this research is limited by its observational nature. A meta-analysis of 7 controlled trials in young, overweight adults with PCOS, shows that taking alpha-lipoic acid 600-1800 mg daily orally for 6-25 weeks, alone or in combination with inositol, reduces fasting blood sugar, and homeostatic model assessment of insulin resistance (HOMA-IR), when compared with control. However, there is no effect on insulin levels, body mass index, lipid profile, or hormone levels (112939).
• Preterm labor. It is unclear if vaginal alpha-lipoic acid is beneficial for preventing preterm birth. Details: Preliminary clinical research shows that administering alpha-lipoic acid 400 mg vaginally once nightly for 30 days after an episode of preterm labor prevents cervical shortening when compared with placebo (96226). It is unclear if these findings are associated with a reduction in the rate of preterm birth.
• Radiation exposure. Oral alpha-lipoic acid might reduce radiation levels in children living in areas contaminated with radiation. Details: Preliminary clinical research shows that taking alpha-lipoic acid 400 mg, alone or in combination with vitamin E (RRR-alpha-tocopherol) 200 mg, daily for 28 days reduces chemiluminescence in leukocytes and urinary radioactivity when compared to baseline in children living in areas contaminated with radiation (21669).
• Schizophrenia. There is mixed evidence regarding the effectiveness of oral alpha-lipoic acid in patients with schizophrenia. Details: A small clinical study in patients with treatment-resistant schizophrenia receiving conventional antipsychotic therapy shows that taking alpha-lipoic acid 300 mg daily for 8 weeks improves scores related to negative symptoms of schizophrenia, but not positive symptoms, when compared with placebo (110114). A very small, open-label study in patients with stable, chronic schizophrenia shows that taking alpha-lipoic acid 100 mg daily along with ongoing antipsychotic medication for 4 months improves symptoms by 64% when compared to baseline. Specific symptom domains, including negative and positive symptoms, excitement, depressive symptoms, and extrapyramidal symptoms all show improvement, although the validity of these findings is limited by the lack of a control group (96228). In contrast, another small clinical study in patients with schizophrenia stabilized on antipsychotic therapy for at least 1 year shows that taking alpha-lipoic acid 100 mg daily for 16 weeks does not improve symptoms of schizophrenia or cognitive function when compared with placebo (110115). Also, a very small, open-label study in patients with schizophrenia shows that taking alpha-lipoic acid 600 mg daily along with conventional antipsychotic therapy for 12 weeks does not improve positive or negative symptoms of schizophrenia when compared to baseline (110116). A meta-analysis of 4 studies in patients with clinically stable schizophrenia does not show any benefit of oral alpha-lipoic acid when compared with placebo, although details of the analysis are limited (112936). Overall, the reasons for the disparate research findings are unclear, but they may be due to differences in the alpha-lipoic acid dose, treatment duration, and severity of schizophrenia across studies. Alpha-lipoic acid has also been evaluated in combination with other ingredients. A small clinical study in patients who responded well to antipsychotic therapy after a single episode of psychosis shows that taking alpha-lipoic acid 150 mg, eicosapentaenoic acid (EPA) 1000 mg, and docosahexaenoic acid (DHA) 500 mg twice daily does not prevent 2-year cumulative relapse or delay relapse time when compared with placebo (90675).
• Sciatica. It is unclear if oral alpha-lipoic acid is beneficial for sciatica. Details: Preliminary clinical research in patients with sciatica secondary to a herniated disc shows that taking alpha-lipoic acid (Byodiniral 300 QR, MDM SpA) 600 mg daily for 60 days improves signs and symptoms of sciatica and decreases the use of analgesics when compared with taking acetyl-L-carnitine (Nicetile, SigmaTau Ind. Farm. Riunite SpA) 1180 mg daily (21671). However, taking alpha-lipoic acid does not affect sleep quality in these patients. Alpha-lipoic acid has also been studied in combination with other ingredients for sciatica. Research in patients with sciatica secondary to a herniated disk shows that taking a combination of alpha-lipoic acid 600 mg with acetyl-L-carnitine, resveratrol, and cholecalciferol orally once daily for 30 days, concurrently with a physiotherapy protocol, reduces pain and disability, and improves quality of life when compared with the physiotherapy protocol alone (112933). Additionally, observational research in patients with sciatic pain due to herniated discs suggests that taking a combination of alpha-lipoic acid 800 mg, myrrh extract 200 mg, and palmitoylethanolamide 600 mg daily for 20 days along with 3 sessions of oxygen-ozone therapy over 30 days is associated with slight improvements in pain when compared with oxygen-ozone therapy alone (111113). It is unclear if the effects are due to alpha-lipoic acid, other ingredients, or the combination.
• Tinnitus. It is unclear if oral alpha-lipoic acid is beneficial for tinnitus. Details: A small observational study in patients with tinnitus associated with cochlear dysfunction and metabolic syndrome suggests that taking alpha-lipoic acid 600 mg for 60 days is associated with improvements in several audiometric parameters and overall tinnitus handicap inventory scores, with a larger effect on functional and emotional scores, when compared to baseline. However, patients with tinnitus secondary to acoustic nerve lesions do not appear to benefit from alpha-lipoic acid supplementation (111705). The validity of these effects is limited by a lack of a comparator group.
• Toxin-induced liver damage. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated with anti-tuberculosis drugs shows that taking alpha-lipoic acid 250 mg, coenzyme Q10 200 mg, and acetyl-L-carnitine 250 mg twice daily for 2 weeks reduces the risk of drug-induced liver injury by 73% when compared with placebo (107445). It is unclear if these findings are due to alpha-lipoic acid, other ingredients, or the combination.
• Vertigo. Oral alpha-lipoic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with benign paroxysmal positional vertigo with serum 25-hydroxyvitamin D levels less than 20 ng/mL shows that taking a specific combination product containing alpha-lipoic acid 600 mg, zinc 7.5 mg, L-carnosine 165 mg, curcumin 100 mg, piperine 1 mg, cholecalciferol 800 units, vitamin B2 0.8 mg, and vitamin B6 1 mg (Vertistop D, Difass) orally daily for 6 months moderately reduces the number of vertigo relapse episodes when compared with control. However, in patients with serum 25-hydroxyvitamin D levels greater than 20 ng/mL that took a specific combination product containing alpha-lipoic acid 600 mg, zinc 7.5 mg, L-carnosine 165 mg, curcumin 100 mg and piperine 1 mg (Vertistop L, Difass) orally daily for 6 months there was no difference in relapse episodes when compared with control (111294). It is unclear if this effect is due to alpha-lipoic acid, other ingredients, or the combination.
• Vitiligo. It is unclear if oral alpha-lipoic acid is beneficial for vitiligo when used in conjunction with phototherapy. Details: When used in combination with phototherapy, clinical research shows that taking alpha-lipoic acid (Shandong Qidu Pharmaceutical Co., Ltd.) 300 mg daily for 6 months does not improve repigmentation when compared with placebo (104654). In contrast, a small clinical study shows that taking two tablets of a specific combination product (Lipoacid Combi, General Topics) containing alpha-lipoic acid 50 mg, vitamin C 50 mg, vitamin E 20 mg, and polyunsaturated fatty acids 12%, starting 8 weeks prior to ultraviolet B phototherapy and continuing for 6 months during phototherapy treatment, seems to increase the likelihood of repigmentation by 29% when compared with placebo (19210). It is not clear if this effect is due to alpha-lipoic acid, other ingredients, or the combination.
• Wilson disease. Although there is interest in using oral alpha-lipoic acid for Wilson disease, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition.
• Wound healing. It is unclear if oral alpha-lipoic acid is beneficial for wound healing. Details: A small clinical study shows that taking a specific alpha-lipoic acid product (Byodinoral 300, M.D.M. Spa) 300 mg one hour before and one hour after hyperbaric oxygen therapy administered daily for 14-30 days reduces wound area in 30% more patients with ischemic ulcers when compared with hyperbaric oxygen therapy alone (21677).
• Wrinkled skin. Although there is interest in using topical alpha-lipoic acid for wrinkled skin, there is insufficient reliable information about the clinical effects of alpha-lipoic acid for this condition. More evidence is needed to rate alpha-lipoic acid for these uses.

(Read more about ALPHA-LIPOIC ACID)

LIKELY EFFECTIVE

• Biotin deficiency. Oral and injectable biotin prevents and treats biotin deficiency. Details: Biotin up to 10 mg daily has been used to treat and prevent biotin deficiency. Injections of biotin 150 mcg daily for 3-5 days have been used in adults. Biotin deficiency might occur due to different etiologies such as inherited biotinidase deficiency, malnutrition, chronic use of anticonvulsants, pregnancy, and excessive and chronic raw egg consumption (6243,19347). A very small study in newborns aged 1-6 months shows that adding biotin to infant formula safely improves biotin status in formula-fed infants (111365). The validity of these findings is limited by a lack of blinding, no randomization, and the small sample size.

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). In spite of contrary reports, high-dose biotin (300 mg daily) does not reduce disability in patients with progressive MS. It also does not seem to be linked to an increased risk for relapse. Details: Although most earlier research suggested benefit, the highest quality evidence shows that high-dose biotin does not improve outcomes in progressive MS (95662,102963,102966,104011). A large multi-centered randomized clinical trial (SPI2) in patients with progressive MS and high disability shows that taking biotin 100 mg three times daily for 15 months does not improve disability, as measured on the expanded disability status scale (EDSS), or 25-foot walking time, when compared with placebo. The SPI2 clinical trial also did not find that biotin increases the rate of relapse (104011), a concern raised in one observational study of high-dose biotin (104000). Also, a large observational study of adults with progressive MS failed to identity an increase in annualized relapse rates in patients that reported taking biotin when compared with controls (105716). Other observational research has also found no effect on the relapse risk (102963,102964). There is some speculation that any increased rate of relapse identified in some high-dose biotin cohorts might be due to detection bias or reduced compliance with disease-modifying therapies.
• Seborrheic dermatitis. Oral biotin doesn't seem to improve seborrheic dermatitis of infancy. Details: A clinical trial in infants with seborrheic dermatitis shows that biotin given by mouth does not improve symptoms when compared with placebo (8469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if oral biotin is beneficial for alopecia areata. Details: A small clinical study in healthy adults with alopecia areata shows that weekly injections of intramuscular biotin 5 mg/1 mL and dexpanthenol 250 mg/2 mL for 6 weeks reduces hair fall count and transiently increases hair density compared with baseline (111366). The validity of these findings is limited by a lack of a placebo control group, small sample size, and short duration of treatment. It is unclear if the effects are due to biotin, dexpanthenol, or the combination. Another small clinical study in 9-year-old children with alopecia areata shows that taking biotin 20 mg with zinc aspartate 100 mg orally along with topical application of clobetasol propionate 0.025% daily for one year promotes hair regrowth in 33% of children, compared with 0% in the group receiving the steroid deflazacort (6932). It is unclear if these effects are due to biotin, zinc, topical clobetasol, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral biotin for ALS, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Biotin-thiamine-responsive basal ganglia disease. Adding oral biotin to oral thiamine does not seem to improve most symptoms associated with this condition, although it may slightly speed recovery from acute crisis in children. Details: A small case series in children ages 1-12 years with biotin-thiamine-responsive basal ganglia disease has found that adding biotin 5 mg/kg daily to thiamine 40 mg/kg daily for 30 months is not associated with additional symptomatic improvement in encephalopathy, seizures, dystonia, or other neurologic sequelae when compared with taking only thiamine. However, taking biotin with thiamine is associated with a 1-day reduction in recovery from acute crisis when compared with thiamine alone (95661).
• Brittle nails. Low quality clinical studies suggest that oral biotin might improve nail thickness and prevent the splitting of brittle nails. Details: Some small, low quality clinical studies in people with brittle nails shows that taking biotin 2.5 mg orally daily for 1.5 to 15 months increases nail thickness and decreases the splitting of fingernails and toenails in some people when compared with baseline (171,35593). The validity of these findings is limited by the small study sizes and the lack of a comparator group.
• Depression. Although there is interest in using oral biotin for mild depression, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Diabetes. It is unclear if oral biotin is beneficial for type 2 diabetes. Details: A meta-analysis of randomized controlled trials shows that taking biotin 1.5-15 mg orally daily for 1-3 months does not improve fasting blood glucose or serum insulin levels when compared with placebo. However, the validity of these results is limited by inclusion of subjects with and without diabetes (110044). A very small study in adults with type 2 diabetes also shows that taking biotin 5 mg three times daily for 28 days does not affect glucose or insulin levels when compared to baseline (11579). Biotin has also been studied in combination with other ingredients. Preliminary clinical research shows that a taking a specific supplement containing a combination of biotin 2 mg and chromium picolinate 600 mcg (Diachrome, Nutrition 21) can lower blood glucose and glycated hemoglobin levels in patients with type 2 diabetes who are poorly controlled on oral hypoglycemic drugs (12385,12390,15169). It is unclear if these effects are due to biotin, chromium, or the combination.
• Diabetic neuropathy. Although there is interest in using oral and intramuscular biotin for diabetic neuropathy, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Muscle cramps. It is unclear if biotin is beneficial for improving muscle cramps in patients undergoing hemodialysis. Details: Patients undergoing hemodialysis are prone to muscle cramps. A small clinical study in patients with hemodialysis-related muscle cramps shows that taking biotin 1 mg in the morning daily for at least one week prevents and reduces severity of muscle cramps when compared to baseline. Cessation of biotin led to recurrence of cramps, and restarting oral biotin led to resolution of cramps during hemodialysis (89475). The validity of these findings is limited by the lack of comparator group. More evidence is needed to rate biotin for these uses.

(Read more about BIOTIN)

LIKELY EFFECTIVE

• Boron deficiency. Oral boron treats and prevents boron deficiency. Details: Taking boron orally is effective for preventing and treating boron deficiency (7135).

POSSIBLY EFFECTIVE

• Radiation dermatitis. Topical application of sodium pentaborate pentahydrate gel to radiation sites may reduce the risk of dermatitis in patients with breast cancer who are receiving radiotherapy. Details: A small clinical study in patients with breast cancer shows that applying a hydrogel containing sodium pentaborate pentahydrate 3% four times daily during radiotherapy for 5 weeks reduces the risk of moderate to severe dermatitis by 50% when compared with petroleum jelly (Vaseline). However, there is no difference in patient satisfaction (95660). Additionally, a larger clinical trial in patients with breast cancer shows that applying a sodium pentaborate pentahydrate 3% gel to radiation sites 15 minutes before each session for 25 sessions reduces the risk of dermatitis by 90%, erythema by 87%, dry desquamation by 92%, and moist desquamation by 97% when compared with a placebo gel (109557).
• Vaginal candidiasis. Boric acid applied intravaginally seems to reduce vaginal candidiasis. Details: Some limited clinical research shows that applying boric acid powder intravaginally 600 mg once or twice daily for up to 3 weeks can treat candidiasis and other vaginal fungal infections, including resistant and chronic infections (15443,15444,15446,15449,15450,15451,15453); however, this research is limited by low study quality. For Candida glabrata yeast infections, which are less prevalent than Candida albicans infections, some evidence shows that intravaginal boric acid capsules are effective in about 65% to 70% of azole-resistant infections; however, boric acid capsules appear to be less effective than intravaginal flucytosine (Ancobon) (15445,15454). For Candida krusei infections, which are rare and resistant to azole antifungal treatment, boric acid capsules also appear to be effective in some cases (15448).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral boron does not seem to improve athletic performance. Details: A small clinical study in male bodybuilders shows that taking boron 2.5 mg daily for 7 weeks does not increase lean body mass, muscle mass, or testosterone levels when compared with placebo (944). Furthermore, the International Society of Sports Nutrition (ISSN) does not recommend boron supplementation as a nutritional ergogenic aid due to a lack of supportive evidence (101009).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral boron is beneficial for age-related cognitive decline. Details: Two very small clinical studies in healthy older adults show that taking boron 3.25 mg daily for up to 49 days orally might improve cognitive function and fine motor skills when compared with lower amounts of boron (943).
• Diabetic foot ulcers. It is unclear if topical boron is beneficial for use in diabetic foot ulcers. Details: A large clinical study in adults with diabetic foot ulcers shows that applying boron (sodium pentaborate 3%) gel twice daily for 1 month marginally reduces ulcer severity, measured by the Wagner Classification system at 25 days and 2 months, when compared with control; recurrence and infection rate were also modestly reduced at 2 months (112423). However, it is unclear whether the analysis controlled for systemic antibiotic use among the two groups, which effects the validity of these findings.
• Dysmenorrhea. It is unclear if oral boron is beneficial for reducing pain during menstruation. Details: A small clinical study in young females with moderate to severe dysmenorrhea suggests that taking boron tetraborate 10 mg daily, starting two days before and continuing until three days after the start of menstruation for two menstrual cycles, reduces pain levels by 24% and pain duration by 1.5 hours, or 34%. Both pain and pain duration were decreased by only 9% in patients receiving placebo (95428).
• Kidney stones (nephrolithiasis). It is unclear if boron is beneficial for medical expulsive therapy after extracorporeal shockwave lithotripsy. Details: A large clinical study in adults undergoing extracorporeal shockwave lithotripsy for kidney stones conducted in Iran shows that taking boron 10 mg twice daily for 2 weeks does not statistically improve the rate of stone expulsion when compared with tamsulosin; however, boron may have fewer side effects (i.e., orthostatic hypotension, headache, nausea, erectile dysfunction) (112414).
• Kidney transplant. It is unclear if oral boron is beneficial in patients receiving a kidney transplant. Details: Observational research in kidney transplant recipients has found that higher boron intake, as measured by urinary boron levels, is associated with a lower risk of mortality when compared with lower intake. Patients with 24-hour urinary boron levels in the top tertile had a 49% lower risk of all-cause mortality when compared with those in the lowest tertile; however, there was no association with graft failure (109556). It is unclear if these findings can be generalized to boron supplements.
• Obesity. Although there has been interest in using oral boron for obesity, there is insufficient reliable information about the clinical effects of boron for this purpose.
• Osteoarthritis. It is unclear if oral boron is beneficial for osteoarthritis symptoms. Details: Small low quality studies in patients with osteoarthritis suggest that taking boron tetraborate 3-6 mg daily for up to 8 weeks might improve pain and other symptoms when compared with a lower intake of boron (941,36870).
• Osteoporosis. It is unclear if oral boron is beneficial for osteoporosis. Details: Preliminary clinical research in postmenopausal adults shows that taking boron 3 mg daily does not improve bone density when compared with placebo (36872).
• Periodontitis. Small clinical studies suggest that adding topical boric acid to scaling and root planing treatment may be beneficial in periodontitis. Details: A meta-analysis of four small clinical studies in 117 patients with periodontitis shows that using boric acid 0.75% gel or solution in addition to scaling and root planing seems to slightly improve probing pocket depth (PPD) and clinical attachment level (CAL) when compared with placebo or saline control (105690). Another small clinical study in patients with periodontitis shows that using boric acid 0.5% for irrigation in addition to scaling and root planing seems to improve CAL and PPD to a similar degree as using povidone-iodine 0.1% (105691). The available research was conducted in Turkey, Vietnam, and India; it is unknown if these findings are generalizable to other geographic locations.
• Tooth extraction. It is unclear if boron is beneficial for use in periodontal healing after impacted third molar surgery. Details: A moderate-sized clinical study in adults 18 to 40 years old shows that using boron 0.1% to 2.5% and chlorhexidine 0.12% mouthwash for 7 days after impacted third molar surgery marginally improves swelling and self-reported pain on day 7, and the higher boron concentrations also improve pain at day 4 when compared with chlorhexidine alone, but does not improve the number of analgesics used or periodontal scores (112379). However, the validity of these results is limited by a lack of statistical adjustment for multiple comparisons which can lead studies to show differences between treatment groups in error (i.e., false positive findings). Additionally, the study period coincides with the expected recovery time (i.e., 2-7 days), making it unclear if any effects are due to the intervention or control. More evidence is needed to rate boron for these uses.

(Read more about BORON)

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplement sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely. Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (BMD), taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

(Read more about CALCIUM)

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CHOLINE)

LIKELY EFFECTIVE

• Chromium deficiency. Oral or parenteral chromium is effective for the treatment and prevention of chromium deficiency. Details: Taking chromium orally is effective for preventing and treating symptoms of chromium deficiency, including hyperglycemia, glycosuria, sudden weight loss, peripheral neuropathy, and confusion (7135).

POSSIBLY EFFECTIVE

• Diabetes. Oral chromium seems to be modestly beneficial for improving glycemic control in diabetes, especially when used in doses greater than 200 mcg daily and in patients with poorly controlled diabetes. It is unclear if chromium helps to prevent the development of diabetes. Details: Epidemiological research has found that lower toenail chromium levels are associated with an increased risk of diabetes and cardiovascular disease (11908). In 2005, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that chromium picolinate may reduce the risk of type 2 diabetes. However, the FDA has determined that any relationship between chromium picolinate and type 2 diabetes is highly uncertain and is based on limited scientific evidence (102362). Research on the use of chromium for the TREATMENT of type 2 diabetes is conflicting but seems to show modest benefit in some patients. Many small clinical studies show that taking chromium orally decreases fasting blood glucose, postprandial glucose, insulin, and glycated hemoglobin (HbA1C) levels, and increases insulin sensitivity (6867,7137,12390,15169,14440,42628,42638,95097,103745). However, other small clinical studies show that chromium is no better than placebo for improving glycemic indices in patients with diabetes (7060,14325,42679,42707,90059,103746,103749). Some of these studies may not have been adequately powered and some had a high risk of bias. Furthermore, these studies had high heterogeneity related to study population and size, chromium supplementation duration, formulation, and dose, and accepted standards of diabetes care. Multiple meta-analyses pooling results of these small clinical trials also show mixed results (90055,90063,95098,105026,110610). The most recent and comprehensive meta-analyses show that chromium picolinate lowers HbA1C by about 0.6%; while it is unclear if chromium yeast, chromium dinicocysteinate, or chromium with biotin or other natural ingredients are beneficial. Chromium seems to be most beneficial in doses of greater than 200 mcg taken for 12 weeks or longer, and in patients with poorly controlled diabetes with a baseline HbA1C of 8% or greater (90063,105026). There is also speculation that chromium might primarily benefit patients with low chromium levels; however, there has not been an analysis specifically evaluating this population (6867,7058,13725,14325,95098). Some research suggests that chromium might also modestly improve lipid levels in patients with type 2 diabetes (1934,6867,95098). A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 42-1000 mcg orally daily for 5-26 weeks decreases triglyceride levels by 7 mg/dL and increases high-density lipoprotein cholesterol levels by 2 mg/dL when compared with control. Taking chromium did not affect low-density lipoprotein cholesterol levels. However, the validity of these results is limited by high heterogeneity (110605). In addition, some meta-analyses have failed to demonstrate any effects of chromium on lipid levels (110610). A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 200-1000 mcg orally daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but not systolic blood pressure or body mass index, when compared with placebo (110607). Preliminary clinical research shows that chromium picolinate might improve metabolic parameters in patients with other forms of diabetes as well. This includes those with type 1 diabetes (1935), diabetes secondary to corticosteroid use (5039,42829), and gestational diabetes (42817).

POSSIBLY INEFFECTIVE

• Hypertension. Meta-analyses of small clinical trials suggest that oral chromium does not lower blood pressure by a clinically meaningful amount. Details: A meta-analysis of randomized clinical trials in adults with different metabolic disorders shows that taking chromium 42-1000 mcg orally daily for 12-24 weeks does not lower systolic or diastolic blood pressure when compared with placebo (110609). A meta-analysis of randomized clinical trials in adults with different chronic disorders shows that taking chromium 42-1000 mcg orally daily for 4-25 weeks lowers systolic and diastolic blood pressure by 3 mmHg and 1 mmHg, respectively, when compared with placebo. However, the validity of this meta-analysis is limited by high heterogeneity (110604). Another meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 200-1000 mcg orally daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but not systolic blood pressure, when compared with placebo (110607). In addition, the validity of these results is limited by inclusion of patients with and without hypertension at baseline (110604,110607,110609).
• Impaired glucose tolerance (Prediabetes). Oral chromium does not seem to improve glycemic indices in patients with prediabetes. Details: Some clinical research shows that adults with impaired glucose tolerance do not have improved glycemic parameters or insulin sensitivity after taking chromium picolinate 500-1000 mcg daily for up to 6 months when compared with placebo (13053,42670). Likewise, a small clinical study in elderly patients with impaired glucose tolerance shows that chromium supplements do not improve glucose tolerance or triglyceride or cholesterol levels when compared with placebo (13722). Finally, a preliminary clinical study in overweight or obese adults with prediabetes shows that taking two capsules of a combination product containing chromium, cinnamon, and carnosine (Glycabiane, PiLeJe) daily for 4 months decreases fasting plasma glucose by approximately 4 mg/dL when compared with placebo, but does not improve fasting plasma insulin, measures of insulin sensitivity or resistance, or glycated hemoglobin (HbA1C) (94234). The small effect on fasting plasma glucose is clinically insignificant and may be due to the other ingredients in this product.
• Schizophrenia. Oral chromium does not seem to improve psychological measures in patients with schizophrenia. Details: Clinical research in patients with schizophrenia shows that taking chromium polynicotinate 400 mcg daily for 3 months does not affect weight or mental status when compared with placebo (42613).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-induced insulin resistance. It is unclear if oral chromium is beneficial for preventing antiretroviral-induced insulin resistance. Details: Preliminary clinical research in HIV patients treated with highly active antiretroviral therapy (HAART) shows that taking chromium nicotinate 200 mcg or chromium picolinate 1000 mcg daily for 8-16 weeks may help decrease insulin resistance and increase glucose disposal when compared to baseline (42630,42662). The validity of this finding is limited by the lack of a control group.
• Athletic performance. It is unclear if chromium enhances athletic performance, although some research suggests that it may improve body composition when used in conjunction with exercise. Details: One large clinical study shows taking chromium 400 mcg daily, in conjunction with resistance training, can increase weight loss, body fat loss, and lean body mass when compared with placebo and resistance training (6868). However, other, very small clinical studies show that adding chromium picolinate or chromium chloride 177-400 mcg daily to a weight-training program does not improve body composition when compared with weight-training alone (6860,6861,6862,42747). These studies may not have been adequately powered to detect a difference in outcomes.
• Atypical depression. It is unclear if oral chromium is beneficial in patients with atypical depression. Details: Preliminary clinical research in patients with atypical depression shows that taking chromium picolinate 400 mcg daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks improves response and remission rates when compared with placebo (10309). However, other clinical research shows that taking elemental chromium 400 mcg in the form of chromium picolinate daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks does not improve most symptoms of atypical depression, although appetite and sexual drive may improve, when compared with placebo (42600).
• Beta blocker-induced dyslipidemia. It is unclear if oral chromium is beneficial in patients with dyslipidemia due to beta-blocker use. Details: One small clinical study in patients who take beta-blockers shows that taking glucose tolerance factor (GTF)-chromium 600 mcg daily for 2 months increases high-density lipoprotein (HDL) cholesterol levels by 16%, but does not affect other lipid parameters, when compared with placebo (5040).
• Binge eating disorder. It is unclear if oral chromium is beneficial in patients with binge eating disorder. Details: One small clinical study in overweight adults with binge eating disorder shows that taking chromium picolinate 600 or 1000 mcg by mouth daily for 6 months does not affect binge eating frequency, body weight, or depressive symptoms when compared with placebo (90057).
• Bipolar disorder. It is unclear if oral chromium is beneficial in patients with treatment-resistant bipolar disorder. Details: Preliminary clinical research in patients with treatment-resistant, rapid-cycling bipolar disorder shows that taking chromium chloride (Hypo-A Chrom, Hypo-A GmbH) 600-800 mcg daily for up to 2 years can decrease the frequency of affective episodes by approximately three episodes annually when compared to baseline (42618). The validity of this finding is limited by the lack of a control group.
• Cognitive impairment. It is unclear if oral chromium prevents cognitive impairment. Details: Some clinical research shows that taking chromium picolinate standardized to contain elemental chromium 1000 mcg daily for 12 weeks does not improve memory or depression in elderly patients with mild cognitive impairment when compared with placebo. However, results from neuroimaging scans suggest that chromium increases the activity of certain regions of the brain during memory tasks when compared with placebo (42666).
• Hyperlipidemia. Small clinical studies suggest that oral chromium may modestly reduce lipid levels in patients with hyperlipidemia. Details: One small clinical study in patients with atherosclerotic disease shows that taking chromium 250 mcg as chromium chloride daily for 7-16 months decreases triglycerides and increases high-density lipoprotein (HDL) cholesterol, but not other lipid parameters, when compared with placebo (7060). Other small clinical studies in adults with hyperlipidemia show that taking chromium picolinate 200 mcg daily for 6 weeks, chromium polynicotinate 200 mcg twice daily, or brewer's yeast containing 48 mcg elemental chromium daily for 6-8 weeks decrease total and low-density lipoprotein (LDL) cholesterol when compared to baseline (37178,42585,42710). The validity of this finding is limited by the lack of comparison with a control group. A meta-analysis of small heterogeneous clinical studies in patients mostly without hyperlipidemia shows that taking chromium orally does not affect lipid levels when compared with placebo (105029). A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 42-1000 mcg orally daily for 5-26 weeks modestly improves triglyceride and HDL cholesterol levels, but not LDL cholesterol levels, when compared with control. However, the validity of these results is limited by high heterogeneity and inclusion of patients with and without hyperlipidemia (110605). In addition, some meta-analyses have failed to demonstrate any effects of chromium on lipid levels in adults with diabetes (110610). Limited research has tested high-dose chromium in children. One small clinical study in children with hypercholesterolemia shows that taking chromium polynicotinate 400-600 mcg with glucomannan 1000-1500 mg twice daily for 8 weeks reduces total and LDL cholesterol when compared to baseline (90061). It is unclear if this effect is due to chromium, glucomannan, or the combination. Finally, chromium does not seem to reduce lipid levels in people without hyperlipidemia.
• Hypoglycemia. It is unclear if oral chromium helps to reverse or prevent hypoglycemia. Details: One very small clinical study in patients with reactive hypoglycemia shows that taking chromium chloride 200 mcg daily for 3 months increases blood glucose levels and improves insulin binding and hypoglycemic symptoms following an oral glucose load (6859). Another small clinical study in patients with symptomatic hypoglycemia shows that taking chromium yeast (Biochrome, Pharma-Nord) 125 mcg daily for 3 months improves symptoms, including chilliness, trembling, and disorientation, when compared with baseline (42711). The validity of this finding is limited by the lack of a control group.
• Metabolic syndrome. It is unclear if oral chromium is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that taking a particular chromium picolinate product (Chromax, Nutrition 21) 500 mcg twice daily for 16 weeks does not affect weight, waist circumference, insulin sensitivity, glycated hemoglobin (HbA1C), or lipid levels when compared with placebo (42654).
• Myocardial infarction (MI). It is unclear if oral chromium helps to prevent MI. Details: Epidemiological research has found that low toenail chromium concentrations are associated with an increased risk of MI (13728). However, toenail chromium concentrations might not be a reliable predictor of body stores of chromium. There is also no reliable research showing that chromium supplements can prevent MI.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral chromium slows NAFLD progression. Details: One small clinical study in patients with NAFLD shows that taking chromium picolinate 200 mcg two times daily after meals for 12 weeks does not affect liver enzyme levels or body weight when compared with placebo (105027).
• Obesity. Although some research suggests that oral chromium may increase weight loss, this increase in weight loss is not likely to be considered clinically relevant. Details: Meta-analyses of clinical studies in overweight or obese adults show that taking chromium picolinate 200-1000 mcg daily for 12-16 weeks might result in a cumulative weight loss of about 0.5-1 kg when compared with placebo (90062,90065). However, this small reduction in weight is unlikely to be considered clinically significant. Furthermore, certain small clinical studies in healthy, overweight or obese adults and children show that taking oral chromium 200-1000 mcg daily for 6-24 weeks does not reduce weight when compared with control (6860,13727,17224,42680). Some of these studies may not have been adequately powered to detect a smaller effect. A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 200-1000 mcg orally daily for 8-25 weeks does not lower body mass index when compared with placebo. However, the validity of these results is limited by inclusion of patients with and without obesity at baseline (110607).
• Polycystic ovary syndrome (PCOS). It is unclear if oral chromium improves symptoms of PCOS. Details: One small clinical study in patients with PCOS shows that taking chromium picolinate 1000 mcg daily for 6 months along with diet and exercise counseling decreases body mass index and improves rates of ovulation and regular menstruation when compared with placebo (95094). Also, some clinical research shows that taking chromium picolinate (21st Century HealthCare, Inc. or Nature Made) 200 mcg daily orally for 8 weeks increases insulin sensitivity when compared with placebo (95095,98687). However, other preliminary clinical research shows that taking chromium picolinate 200 mcg daily for 4 months does not affect insulin sensitivity or improve ovulation rates (42603). Although chromium picolinate at doses of less than 1000 mcg might have very small effects on fasting glucose, these doses do not seem to have clinically beneficial effects on fasting glucose, pregnancy rate, or testosterone levels (95094,95095,98687). A lower dose of chromium has also been studied in combination with carnitine. One small clinical study in overweight adults with PCOS shows that taking chromium picolinate 200 mcg daily with carnitine 1000 mg daily for 12 weeks modestly reduces fasting blood glucose, insulin resistance, and body weight, and slightly increases insulin sensitivity, when compared with placebo (103747). However, it is unclear if this benefit is clinically significant. Additionally, it is unclear if these effects are due to chromium, carnitine, or the combination. Carnitine has demonstrated clinical benefit when used alone in PCOS.
• Turner syndrome. It is unclear if oral chromium is beneficial in patients with this condition. Details: A small clinical study shows that taking brewer's yeast 30 grams containing chromium 50 mcg daily for 8 weeks might improve abnormalities in glucose and lipid metabolism when compared with baseline in patients with Turner syndrome, a genetic disorder that has a high incidence of diabetes (13729). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate chromium for these uses.

(Read more about CHROMIUM)

LIKELY EFFECTIVE

• Copper deficiency. Oral or intravenous copper is beneficial for treatment of copper deficiency. Details: Taking copper orally or intravenously is effective for treating copper deficiency and anemia due to copper deficiency. Copper deficiency is rare. It is seen most commonly in people receiving prolonged parenteral nutrition (7135). Oral cupric sulfate has been used in doses up to 0.1 mg/kg daily (7135). Copper 1-2 mg per day in parenteral nutrition solution has also been used (505).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Oral copper does not seem to be beneficial for Alzheimer disease. Details: Preliminary clinical research shows that taking copper orotate dihydrate, providing 8 mg of elemental copper, daily for 12 months does not improve scores on evaluation scales for Alzheimer disease when compared with placebo (45949). There is also some concern that copper could have detrimental effects. Observational research has found that people with Alzheimer disease have higher levels of copper in their blood than people without the disease (95917); the clinical significance of this finding is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral copper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing copper (NicAzel, Elorac Inc.) 1-4 tablets daily for 8 weeks reduces inflammatory lesions in patients with inflammatory acne when compared with baseline. Other ingredients in this product include nicotinamide, azelaic acid, zinc, pyridoxine, and folic acid; specific quantities are not known (90800). The validity of this finding is limited by the lack of a comparator group.
• Brain tumor. It is unclear if oral copper is beneficial for use in glioblastoma. Details: A moderate-sized open-label clinical study in adults with first recurrence of glioblastoma receiving alkylating chemotherapy shows that taking elemental copper 2.5 mg with disulfiram 400 mg daily for 6 months does not improve survival but does result in significantly more adverse effects (e.g., elevated liver enzymes) when compared with control. The trial was stopped early due to safety concerns (112376).
• Cardiovascular disease (CVD). Although there is interest in using oral copper for CVD prevention, there is insufficient reliable information about the clinical effects of copper for this purpose.
• Chemotherapy-induced acral erythema. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 acral erythema (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced anemia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 anemia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced diarrhea. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 diarrhea (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced leukopenia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 neutropenia or febrile neutropenia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced nausea and vomiting (CINV). Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 vomiting (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chronic venous insufficiency (CVI). It is unclear if compression stockings containing copper are beneficial for lipodermatosclerosis in patients with CVI. Details: Preliminary clinical research shows that using compression stockings impregnated with copper for 8 weeks does not improve overall symptoms of lipodermatosclerosis secondary to chronic venous disease when compared with using a compression stocking without copper. However, the affected surface area may be reduced by approximately 16% by 2 weeks when copper-impregnated compression stockings are used (101809).
• Dental plaque. It is unclear if rinsing the mouth with copper is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing the mouth with a solution of copper 1.1 mmol/L for 4 days decreases plaque accumulation when compared with a placebo solution (46006).
• Diarrhea. Oral copper has only been evaluated in combination with zinc; its effect when used alone is unclear. Details: Preliminary clinical research in children 6 months to 5 years of age presenting to a hospital in India with acute watery or bloody diarrhea shows that taking a solution providing zinc 2 mg/kg and copper 0.2 mg/kg orally daily for 2 weeks does not reduce the duration of diarrhea, the weight of stool, or the need for rehydration when compared with placebo (87166). It also does not seem to reduce the recurrence of diarrhea or improve weight gain over the next 3 months (95540).
• Oral mucositis. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 oral mucositis (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Osteoarthritis. Although there is interest in using topical copper for osteoarthritis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Osteoporosis. Oral copper has only been evaluated in combination with other minerals; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking copper 2.5 mg in combination with zinc 15 mg, manganese 5 mg, and calcium 1000 mg daily for 2 years can slow bone loss when compared with taking either calcium or the trace minerals alone (1994).
• Postoperative infection. It is unclear if copper-impregnated wound dressings are beneficial for the prevention of postoperative infection. Details: Preliminary clinical research shows that using a wound dressing impregnated with copper oxide 3% by weight reduces the incidence of a surgical site infection in the 30-day period following a caesarean section by 39%, but does not reduce length of hospital stay or readmission rate, when compared with a non-copper wound dressing. Eight patients would need to be treated with the copper-impregnated dressing to prevent one infection (105363). This study is limited by the use of a telephone questionnaire to assess the suspicion of infection.
• Systemic lupus erythematosus (SLE). It is unclear if oral copper is beneficial for improving symptoms of SLE. Details: Copper status does not appear to be associated with the risk of SLE (101810). Additionally, one small clinical study shows that taking copper 3 mg daily, alone or in combination with fish oil, for 24 weeks does not affect symptoms of SLE when compared with placebo (12953).
• Tinea pedis. Although there is interest in using topical copper for tinea pedis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Wound healing. It is unclear if topical copper sulfate can improve the healing of umbilical granuloma. Details: A small clinical study in children 1-3 months of age with treatment-naïve umbilical granuloma shows that a single application of copper sulfate to the affected site results in complete resolution in 70% of patients, compared with 90% of patients receiving topical sodium chloride twice daily for 5 days. Some patients who received a second application of copper sulfate experienced full healing; however, it is unclear if this was due to the treatment or natural resolution (109403). More evidence is needed to rate copper for these uses.

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EFFECTIVE

• Folate deficiency. Oral or intravenous folic acid is effective for the prevention or treatment of folate deficiency. Details: Administering folic acid orally or parenterally improves and prevents folate deficiency (505,8739). Clinical research shows that supplementation with folic acid 100 mcg to 5 mg daily during pregnancy decreases the risk of developing megaloblastic anemia by up to 79% (91307).

LIKELY EFFECTIVE

• Kidney failure. Taking folic acid orally reduces homocysteine levels in people with kidney failure who are on hemodialysis. Details: Over 85% of people with kidney failure have hyperhomocysteinemia. Treatment of hyperhomocysteinemia in kidney failure is often more difficult than with normal kidney function (1489,3324,7289,9413,9414,9416). The reasons for this are not fully understood; renal uptake and metabolism of homocysteine may be reduced in severe kidney failure, and hemodialysis may contribute to vitamin deficiencies (6884,9414,9417). Folic acid 0.8-15 mg daily or 3 times weekly is generally used, but the degree of homocysteine reduction varies between 12% to 50%, and normal homocysteine levels (less than 12 µmol/L) cannot always be achieved. Adding vitamin B12 400-1000 mcg daily and vitamin B6 20-50 mg daily produces an additional reduction in homocysteine (1489,6884,7289,7881,9322,9413,9414,9415,9416,9417). Folic acid doses greater than 15 mg daily do not seem to provide additional benefit. Also, doses of 30-60 mg might cause a rebound in homocysteine levels when treatment is stopped (9219). Despite the homocysteine-lowering effect of folic acid in kidney failure, the most robust meta-analysis of 11 clinical trials suggests that folic acid supplementation does not seem to reduce the risk of cardiovascular events (50527). A smaller meta-analysis of 7 clinical trials that used a different primary composite outcome suggests that folic acid might reduce the risk of cardiovascular events by 15% when compared with control (91311). There has also been interest in using a reduced form of folic acid, L-5-methyltetrahydrofolate (L-5-MTHF). One study in patients on hemodialysis suggests that taking L-5-MTHF 17 mg daily for 12 weeks might lower homocysteine levels to a greater extent than an equimolar 15 mg of folic acid (104908). Another clinical trial in patients on hemodialysis suggests that giving intravenous L-5-MTHF 50 mg three times weekly is associated with an increased survival of about 36 months, compared with about 26 months with folic acid 5 mg daily. There was no difference in homocysteine reduction between groups (104909). These results should be interpreted with caution because they have not been replicated, and there was no placebo control. Furthermore, survival may have been affected by the availability of kidney transplants.
• Hyperhomocysteinemia. Oral folic acid, taken alone or in combination with other B vitamins, lowers homocysteine levels in most patients. However, it is unclear if this has cardiovascular benefits. Details: Taking folic acid orally 0.4-5 mg daily lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels at baseline. Folic acid 0.8-1 mg daily seems to provide maximal reduction (9307,9400,9401,9405,9408,11337,11338,50145). Doses above 1 mg daily do not seem to add benefit (9307), except in some people with certain gene mutations that cause homocysteine levels of 20 µmol/L or higher (9408). The higher the initial homocysteine levels, the lower the folic acid dose needed to attain maximum homocysteine reduction (9307). The effects of folic acid supplementation on homocysteine concentrations appear to be greater in females than males (50145). Adding vitamin B6 25-250 mg or vitamin B12 500 mcg seems to further reduce homocysteine levels (1489,9400,9405,9406,9408,107136). Some experts recommend routine use of vitamin B12 in homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Increasing folic acid intake with supplements or folate-fortified cereal products is more effective for reducing homocysteine levels than increasing intake of folate-rich foods (6367). Fortification of cereals and flour with 140 mcg folic acid per 100 grams reduces the mean homocysteine level in the general population by about 7% (7881,9404,9407). Elevated homocysteine levels are considered by some to be an independent risk factor for atherosclerosis progression, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, ischemic stroke, and other vascular complications (3886,3887,6236,7725,9314,9318,50509). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). Although folic acid lowers homocysteine levels, it is not yet known whether this reduces the risk of vascular disease. One meta-analysis shows that taking folic acid can reduce the risk of stroke by about 10% in patients with cardiovascular disease (CVD); the reduction is greatest in patients for whom homocysteine levels are lowered by at least 25% (96157). A meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). However other research does not agree. Meta-analyses of clinical research show that folic acid does not prevent CVD or coronary heart disease, in spite of lowering homocysteine by up to 55%, when individuals with normal or high levels of homocysteine are considered (50539,96147,97619). Furthermore, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or improve secondary prevention of cardiovascular events such as myocardial infarction in people with existing CVD despite a homocysteine-lowering effect (9313,11337,11387,13482,50437,97619). Some research even suggests an increase in CVD risk concurrent with homocysteine lowering (13482). Large randomized controlled trials are needed to confirm or refute these findings. Some researchers hypothesize that different genetic profiles might explain some of these conflicting results. For instance, individuals with a homozygous 677TT MTHFR genotype typically have increased homocysteine levels. However, a meta-analysis suggests that treatment with folic acid does not reduce the risk of ischemic heart disease despite reducing homocysteine levels in individuals with 677TT MTHFR (50456). It has also been theorized that a reduced form of folic acid, 5-methyltetrahydrofolate (5-MTHF) might work better in these individuals. Although [6RS]-5-MTHF has been shown to lower homocysteine levels (104915), studies assessing its cardiovascular benefits are lacking.
• Methotrexate toxicity. Oral folic acid reduces the severity of methotrexate toxicity. Details: Oral folic acid reduces methotrexate toxicity symptoms, such as nausea and vomiting, in the treatment of rheumatoid arthritis (RA) and psoriasis (768,2162,2163,2164,4492,4493,4494,9369,9419). Folic acid also seems to reduce methotrexate-induced hepatic side effects by approximately 36% (50320). Some research shows that a low, 0.8 mg weekly dose of folic acid is equally effective to a higher dose of 5 mg weekly for the prevention of methotrexate toxicity (102388).
• Neural tube birth defects. Oral folic acid helps to prevent neural tube birth defects in newborns. Details: Clinical practice guidelines recommend that anyone capable of becoming pregnant take folic acid 400 mcg daily from fortified foods or supplements to prevent neural tube birth defects in infants. Folic acid 600 mcg daily is advised during pregnancy (94811,96146). This recommendation is based on research showing that a higher intake of folic acid from food and supplements during pregnancy reduces the primary incidence of neural tube birth defects by 41% to 69% (3325,9309,50344,50403,50468,95156). Individuals with a history of children with neural tube birth defects usually take a higher dose of folic acid 4000 mcg daily starting one month before and continuing for up to 3 months after conception (96146). Evidence shows that, when used for secondary prevention, folic acid supplementation reduces the incidence of neural tube defects by 66% to 87% (21235,50263,50344,50403,95156). In the US, foods containing at least 60 mcg of folic acid can be labeled with a health claim stating that healthful diets with adequate folic acid intake may reduce the risk of having a child with a brain or spinal cord defect (102369).

POSSIBLY EFFECTIVE

• Cognitive impairment. Taking folic acid alone, with other B vitamins or with docosahexaenoic acid (DHA), might improve thinking and memory skills in older patients with cognitive impairment. Details: One clinical trial in patients aged 65 years and older with mild cognitive impairment (MCI) shows that taking folic acid 400 mcg daily for 2 years increases IQ scores when compared with placebo (100952). Two small, low-quality clinical studies in patients aged 70-90 years with cognitive impairment and low folate levels or folate deficiency shows that taking folic acid 5 or 15 mg daily for up to 63 days improves cognitive function, including measures such as memory and attention, when compared with placebo or baseline (50301,104911). Folic acid also appears to be beneficial when used in combination with other B vitamins or with DHA. A clinical trial in patients aged 70 years and older with MCI shows that taking folic acid 800 mcg, vitamin B6 20 mg, and vitamin B12 500 mcg daily for 2 years mitigates decline in executive function and, in patients with high baseline homocysteine levels, improves cognition and memory when compared with placebo (50480). Taking folic acid 800 mcg with or without DHA 800 mg daily for 6 months modestly improves cognition, as measured on the full-scale intelligence quotient, when compared with placebo (103978,109196). However, this benefit is no longer present at 6 months after treatment discontinuation (109196).
• Depression. Oral folic acid seems to modestly reduce depression severity when added to conventional antidepressant therapy. It is unclear if folic acid can reduce the prevalence of depression or the risk for suicide. Details: Observational studies suggest that depression is correlated with low folate status, particularly in females (50105,50127,50243). Taking folic acid 0.2-15 mg daily for up to 6 months with conventional antidepressants seems to improve treatment response in patients with major depressive disorder (3657,10884,10887,50566,109190). One meta-analysis shows that taking L-methylfolate or folic acid as an adjunct to treatment with conventional antidepressants modestly reduces depression severity when compared with placebo and conventional antidepressants. The response and remission rates were improved by 36% and 39%, respectively (109190). However, limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy (10886). Also, a small clinical study in adolescents at high familial risk for mood disorders suggests that taking folic acid 2.5 mg daily for up to 36 months does not prevent mood disorders when compared with placebo. However, in the patients that were eventually diagnosed with depression, the time of onset was delayed from 5 months to 15.5 months in the group using folic acid when compared with placebo (91313). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that folic acid is not currently recommended as monotherapy treatment for unipolar depression (110318). Observational research has also evaluated the association between folic acid supplementation and suicidal events in patients with or without depression. One within-person cohort study, in which only 12% of patients were diagnosed with depression, has found that filling a folic acid prescription of 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a reduced risk for suicidal events during the following months when compared with months without a prescription (109201). It is unclear what percentage of these patients, if any, had folate deficiency at baseline.
• Hypertension. Oral folic acid seems to modestly reduce hypertension. Details: A meta-analysis of clinical research shows that taking folic acid 5-10 mg daily for at least 6 weeks reduces systolic blood pressure by 2mmHg and improves flow-mediated dilation by 1.6% in hypertensive individuals (50364). Some research has evaluated folic acid in hypertensive patients when used with antihypertensive drugs. Results show that taking folic acid 400-800 mcg in combination with enalapril 10 mg daily for about 4.5 years does not improve blood pressure when compared with enalapril alone (50302,96158). However, in hypertensive patients with heavy proteinuria, this combination seems to reduce the risk of all-cause mortality by about 41% when compared with enalapril alone (96158).
• Phenytoin-induced gingival hyperplasia. Topical folic acid seems to reduce gingival hyperplasia due to phenytoin. The effect of oral folic acid is unclear. Details: Applying folic acid topically seems to inhibit gingival hyperplasia secondary to phenytoin therapy (2151). However, taking folic acid orally does not seem to improve gingival hyperplasia secondary to phenytoin therapy in adults (2150,2151,2152), although some evidence suggests that taking folic acid 500 mcg daily reduces the risk of phenytoin-induced gingival hyperplasia by 33% in children when compared with placebo (50463).
• Stroke. Although some clinical research has shown that oral folate reduces stroke risk by a small amount, more research is needed to determine who is most likely to benefit. Most individual clinical trials show that folic acid seems to reduce stroke risk only in regions without food-fortification policies. Details: Multiple clinical studies have shown that folic acid supplementation reduces the risk of stroke by 10% to 25% in regions WITHOUT established policies mandating folic acid fortification of grain products (50240,50485,50525,50539,91325,96154,96157,96159,97308). The effect appears to be greatest when folic acid is taken in low doses (usually 0.8 mg daily or lower) (50525,96157,96159), in regions with a low prevalence of statin use (50525,96159), in patients with high cholesterol levels at baseline (96152), in patients who achieve homocysteine reduction of at least 20% (50407,96157), and in patients with the lowest folate levels at baseline (96154,96157). There is also some evidence that the effect of folic acid on stroke risk is greatest in patients with low baseline levels of vitamin B12 (96159). In 2001, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Most research shows that folic acid supplementation does not reduce the risk of stroke in regions WITH established policies mandating folic acid fortification (50240,50485,50525,50539,96157,96159,97308). However, there is some evidence that folic acid may reduce the risk of stroke in patients from regions with folic acid fortification who have recently had a stroke or transient ischemic attack and are not using antiplatelet drugs (90379). Meta-analyses of clinical research have been conducted. However, possible confounding due to the presence or absence of folic acid fortification is unclear. A meta-analysis of the available research in adults with existing CVD shows that folic acid supplementation at a daily dose of less than 2 mg reduces the risk for stroke by about 10% (102386). Also, a meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke by 10% when compared with placebo (97619). In patients with a history of stroke, a meta-analysis shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). It is unclear if folic acid reduces the stroke risk in patients with impaired kidney function. Some research shows that taking folic acid in combination with high doses of vitamin B12 (cyanocobalamin) does not reduce the risk of stroke in these patients (11387,96150). However, there is concern that the lack of benefit may have been due to the decline in kidney function from high doses of cyanocobalamin (96150). Additional research is needed to determine if folic acid supplementation is beneficial in patients with impaired kidney function when used with other forms of vitamin B12 such as methylcobalamin or hydroxycobalamin.
• Vitiligo. Oral folic acid seems to improve vitiligo symptoms. Details: Taking folic acid orally seems to improve symptoms of vitiligo (2153,2154). This finding is supported by a meta-analysis of observational research which shows that patients with vitiligo have higher serum homocysteine levels when compared with patients without vitiligo (100951).

POSSIBLY INEFFECTIVE

• Anemia. Adding oral folic acid to oral iron therapy does not seem to improve hematologic parameters in patients with anemia. Details: In postpartum patients with anemia, clinical research shows that taking iron as ferrous fumarate 600 mg and folic acid 1 mg daily is no more effective than iron alone for improving hemoglobin status (91319). Also, clinical research in non-pregnant menstruating females shows that taking folic acid 0.4 mg daily or 2.8 mg once weekly for 16 weeks with iron 60 mg daily does not reduce anemia or improve iron status when compared with iron alone (109193). During pregnancy, clinical research shows that folic acid supplementation does not decrease the risk of pre-delivery anemia or low hemoglobin levels (91307).
• Age-related cognitive decline. Oral folic acid does not seem to prevent cognitive decline in healthy elderly adults. Details: Most clinical research shows that taking folic acid, alone or in combination with other B vitamins, does not improve cognitive function, including memory, language, or executive function, in elderly adults with age-related cognitive decline (50318,50412,50510). In fact, a large-scale observational study in the US has found that people over 65 years of age who consume large amounts of folic acid (median of 742 mcg daily) have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg daily) (13068). While most research on folic acid for age-related cognitive decline lacks positive findings, many of the studies are small, short-term (<1 year), underpowered to detect significant differences, and not specific to patients with high homocysteine levels. Population research has found that high homocysteine levels are associated with decreased cognition in older adults, suggesting that using folic acid to lower homocysteine levels might mitigate cognitive decline in these patients (50094). Two long-term clinical trials examining the effects of folic acid in elderly adults with high homocysteine levels show mixed results. A large-scale clinical trial of patients aged 50-70 years from the Netherlands who have high homocysteine levels shows that taking folic acid 800 mcg daily for 3 years increases memory, information processing, and other measures of cognitive function when compared with placebo (15271). However, another large-scale clinical trial of patients aged 65 years and older from the Netherlands who have high homocysteine levels shows that taking folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years lowers homocysteine levels, but does not appear to improve overall measures of cognitive function, when compared with placebo (90392). The reasons for the discrepant findings in these two studies are not clear but might relate to differences in the dose of folic acid, duration of treatment, and age of patients included.
• Cataracts. Oral folic acid does not seem to reduce cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or with risk factors for CVD shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of developing cataracts. Furthermore, the risk of cataract extraction was increased by 28% in these patients (96149).
• Diarrhea. Oral folic acid does not seem to reduce the risk of diarrhea, and might even increase the incidence of diarrhea in children. Details: In children aged 6-30 months at risk of malnourishment, clinical research shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of diarrhea when compared with placebo. Enrichment with folic acid, with or without vitamin B12, actually seems to increase the likelihood of having more episodes of both persistent diarrhea and diarrhea lasting over 3 days (90391).
• Fall prevention. Oral folic acid does not seem to reduce the risk of falls. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily, for 2 years, does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Fetal and premature infant mortality. Oral vitamin B12 does not seem prevent mortality in premature infants. Details: Clinical research shows that supplementation with folic acid during pregnancy does not decrease the risk of miscarriage, stillbirth, or neonatal death (91307,96156).
• Leukemia. Oral vitamin B12 does not seem to reduce the risk for pediatric acute lymphoblastic leukemia. Details: A meta-analysis of results from two case-control studies has found that increased folate intake during pregnancy is not associated with a reduced risk of childhood acute lymphoblastic leukemia (50247).
• Male infertility. Oral folic acid does not seem to improve sperm parameters or pregnancy rates in males with infertility. Details: Some small clinical studies show that taking folic acid, alone or with zinc, increases sperm count in males with idiopathic infertility or in males with a grade III varicocele (9334,90194). However, another small study in males with asthenozoospermia shows that taking folic acid 5 mg, selenium 200 mcg, and vitamin E 400 IU daily for 3 months does not improve sperm parameters when compared with placebo (104907). Furthermore, there seems to be no improvement in clinical outcomes. One large, high-quality clinical study in males with idiopathic infertility shows that taking folic acid 5 mg with zinc 30 mg daily for 6 months does not improve sperm morphology, pregnancy rate, or live birth rate when compared with placebo (102085). Folic acid has also been evaluated in combination with other ingredients. A retrospective study in males with or without varicocele-related infertility suggests that taking a specific combination product containing folic acid 0.2 mg, vitamin C, zinc, L-carnitine fumarate, acetyl-L-carnitine, coenzyme Q10, selenium, and vitamin B12 (Proxeed Plus, Sigma-Tau) twice daily for 6 months is associated with improvements in sperm count, sperm concentration, and sperm motility when compared to baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles (111296). The validity of this study is limited by the lack of a comparator group.
• Osteoporosis. Oral folic acid does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly adults or adults with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral folic acid does not seem to improve physical performance in older adults. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years, does not improve hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).
• Pre-eclampsia. Oral folic acid does not seem to prevent pre-eclampsia in pregnant patients. Details: While the effect of low-dose prenatal folic acid is unclear, high-dose folic acid does not seem to reduce the risk of pre-eclampsia. Some population research has found that low-dose folic acid is associated with a 22% reduced odds of pre-eclampsia, while other research has found no association (91308,99370,99372,110447). A large clinical trial evaluating high-dose folic acid in pregnancies at risk for pre-eclampsia shows that taking 4 mg daily, starting at 8-16 weeks of gestation and continuing until delivery, does not reduce the risk of pre-eclampsia when compared with placebo (103929). A secondary analysis of this study in twin pregnancies has also found no benefit with high-dose folic acid supplementation (103977).
• Respiratory tract infections. Oral folic acid does not seem to prevent respiratory tract infections. Details: Clinical research in children aged 6-30 months at risk of malnourishment shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of lower respiratory infections when compared with a supplement not enriched with folic acid and vitamin B12 (90391).

LIKELY INEFFECTIVE

• Colorectal adenoma. Oral folic acid does not prevent colorectal adenomas. Details: Although some population research and one clinical study has found that high folate intake is associated with reduced colorectal adenoma risk (2142,2143,91303), most clinical research does not support this finding. Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for up to 9.2 years, does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389). Other clinical research suggests that taking folic acid does not reduce the occurrence or recurrence of adenomas or incidence of advanced adenomas (34596,50241,50265,50369,50394,50449,50522). Furthermore, treatment with folic acid for more than 3 years seems to be associated with an increased risk of advanced adenomatous lesions (50378).
• Fragile X syndrome. Oral folic acid does not improve symptoms in children with fragile X syndrome. Details: Clinical research shows that taking folic acid orally does not improve symptoms of fragile X syndrome (2155,2156,2157,2158,2159,2160,50575).
• Preterm labor. Oral folic acid does not seem to reduce the risk of preterm birth. Details: Meta-analyses of clinical research show that supplementation with folic acid 200 mcg to 5 mg during pregnancy does not decrease the risk of preterm birth (91307,96155). An observational study in patients with and without epilepsy found that folic acid supplementation during pregnancy was associated with a lower odds of preterm birth in patients receiving antiseizure medications; however, no link between folic acid and preterm labor was reported in patients without epilepsy or in those with epilepsy not receiving antiseizure medications (110447).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal wall defects. It is unclear if oral folic acid helps to prevent abdominal wall defects in newborns. Details: Observational research in a population in northern China has found that taking folic acid supplements until the end of the first trimester modestly reduces the risk of abdominal wall defects and the risk of omphalocele, specifically, in the newborn when compared with not taking folic acid. However, this association was not found in a population in southern China (109191). These differing outcomes may be related to the lower dietary folate intakes in northern China.
• Acne. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing folic acid, vitamin B6, nicotinamide, azelaic acid, zinc, and copper for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared with baseline (90800).
• Age-related macular degeneration (AMD). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to folic acid, other ingredients, or the combination.
• Age-related testosterone deficiency. Folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Alzheimer disease. It is unclear if oral folic acid reduces the risk of developing this condition. Details: Low levels of folate and high levels of homocysteine have been linked to a greater risk of Alzheimer disease (50094). Also, some observational studies have found that higher intake of folate from the diet and supplements in elderly adults is associated with a reduced risk of developing Alzheimer disease when compared with lower intake (13165,15270). One small clinical trial in patients with Alzheimer disease who are taking cholinesterase inhibitors shows that taking folic acid 1 mg daily for 6 months increases the likelihood of treatment response, classified as global improvement in behavioral and/or functional status with no decline in mental status scores, by 78% to 87% when compared with placebo (50246). Also, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). However, not all research agrees. Clinical research in patients with probable Alzheimer disease using routine medications shows that taking folic acid 5 mg, vitamin B12 1 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo (50319). However, all patients in this study were also consuming a folate-fortified diet.
• Angioplasty. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that folic acid 1 mg, vitamin B12 400 mcg, and pyridoxine 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151).
• Atopic dermatitis (eczema). It is unclear if oral folic acid during pregnancy reduces the risk of eczema in the child. Details: Observational research has found that consuming both iron and folic acid supplements during pregnancy is associated with a four-fold reduced risk for developing atopic dermatitis in the child. However, use of either iron or folic acid supplementation alone is not associated with an effect on the child's risk for atopic dermatitis (102387).
• Autism spectrum disorder. It is unclear if oral folic acid intake during pregnancy reduces the risk of autism spectrum disorder in the child. Details: A meta-analysis of population research has found that consumption of folic acid of at least 400 mcg daily from both diet and supplements during pregnancy is associated with a 45% reduced risk of autism in the child at 2-15 years of age. Also, supplementation with folic acid during the prenatal to early period of pregnancy is associated with an approximate 43% reduced risk of autism in the child. This association did not differ between countries with or without a folate fortification program (109198). An individual population study has also found that prenatal folic acid supplementation initiated the first day of the last menstrual period before conception is associated with a 39% reduced odds of autism in the child at age 3.3-10.2 years when compared to pregnancies without folic acid supplementation (91324).
• Beta-thalassemia. There is limited evidence on the oral use of folic acid for beta-thalassemia minor. Details: Patients with beta-thalassemia minor may experience decreased muscle strength and increased bone or muscle pain. A small clinical study in children with this condition shows that taking folic acid 1 mg, with or without L-carnitine 50 mg/kg, daily for 3 months reduces bone pain by 64% to 84% and increases the number of stairs climbed by 2- to 5-fold when compared with baseline (90631). The validity of this finding is limited by the lack of a control group.
• Bipolar disorder. It is unclear if adding oral folic acid to conventional bipolar therapy further improves symptoms. Details: Some clinical evidence suggests that folic acid does not improve the antidepressant effects of lithium in patients with bipolar disorder (50566). However, other clinical evidence suggests that taking folic acid in combination with valproate during the acute phase of mania improves the effects of valproate (50357).
• Breast cancer. It is unclear if oral folic acid reduces breast cancer risk. Details: Some older population research suggests that increased intake or levels of folic acid alone does not affect the risk of breast cancer or breast cancer-related mortality (50218,50224). However, in a specific group of women who also consume high amounts of dietary methionine, cyanocobalamin (vitamin B12), or pyridoxine (vitamin B6), dietary intake of folate is associated with a reduced risk of breast cancer (9328,50224). Also, more recent population research has found that folic acid plus folate dietary intakes between 153-400 mcg are associated with a reduced risk of breast cancer. This risk is further reduced in those who drink relatively large amounts of alcohol (90794). Folate intakes greater than 400 mcg daily do not appear to be protective against breast cancer (90794).
• Cancer. It is unclear if oral folic acid prevents cancer. Details: A large cohort study of children born to mothers with epilepsy on antiseizure medications suggests that prenatal folic acid exposure of 1 mg daily or more, at an average of 4.3 mg daily, is associated with a 2.7-fold greater risk of pediatric cancer when compared with children born to mothers with epilepsy but without prenatal exposure to high-dose folic acid. Additionally, this risk is not present in children of mothers without epilepsy taking high-dose folate (112103). It is unclear how maternal epilepsy, antiseizure medications, and folate interact to increase the risk of pediatric cancers. However, in the absence of clear guidelines, mothers with epilepsy should take no more than 4 mg of folic acid daily (112101,112102).
• Cardiovascular disease (CVD). Although oral folic acid does not seem to prevent most CVD events, some research suggests that increased dietary folic acid might lower the risk of stroke and CVD-related mortality in patients at high risk for CVD. Details: In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Meta-analyses of available research show that folic acid might lower the risk of stroke in patients with CVD (97619,102386,107136). Some clinical research shows that taking folic acid reduces the risk of CVD by 15% in patients with kidney failure or chronic kidney disease (50444,91311). However, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or reduce the risk of death or CVD events in patients with existing hyperhomocysteinemia, coronary heart disease, CVD, kidney disease, or prior stroke, despite having a homocysteine-lowering effect (9313,9322,11337,11387,13482,50437) (50512,50527,96154,96147,97619,102386). Some population research has evaluated adults at high risk for CVD. This research has found that dietary folate intake of at least 382 mcg daily is associated with a modest reduction in CVD-related mortality and possibly all-cause mortality. Consuming folic acid as a component of fortified food in doses of more than 251 mcg daily is associated with a modest reduction in CVD-related mortality. Conversely, folic acid supplementation is associated with a higher risk of CVD and overall mortality, and there is a J-shaped association between folate intake, serum folate levels, and red blood cell folate levels, with both CVD-related and all-cause mortality (109199).
• Cervical cancer. It is unclear if oral folic acid prevents cervical cancer. Details: Epidemiological evidence has found that increasing folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might decrease the risk of precancerous cervical lesions (11074).
• Child development. It is unclear if oral folic acid supplementation during pregnancy improves child development. Details: Clinical research in Northern Ireland shows that taking folic acid 400 mcg daily starting in the 14th week of gestation and continuing until the end of pregnancy improves word reasoning in the child at 7 years of age when compared with placebo. When compared with a historical cohort from Britain, folic acid supplementation was associated with an increase in full scale IQ, verbal IQ, performance IQ, and general language at 7 years of age (102385). At age 11, benefits in word reasoning were no longer significant. However, there were modest benefits in some measures of processing speed when compared with placebo. Verbal comprehension was modestly improved in females, but not males (109192). Observational research in pregnant individuals and their children in Spain has found that taking less than 400 mcg of folic acid daily during pregnancy is associated with lower mental alertness scores in children at ages 7-9 years when compared with folic acid 400-999 mcg daily, while taking folic acid 1000 mcg or more daily during pregnancy was associated with improvements in some measures of working memory in the children. However, no relationship between folic acid dosing and most other measures of cognitive function was identified (110449).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral or injectable folic acid for CFS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Chronic kidney disease (CKD). While adding oral folic acid to enalapril might slow CKD progression, adding folic acid to high-dose vitamin B12 does not seem to be beneficial. Details: Clinical research in adults with hypertension and CKD shows that taking enalapril with folic acid 800 mcg for a median of 4.4 years reduces the risk of worsening kidney function by 21% and slows the rate of kidney function decline by 44% when compared with enalapril alone (96153). However, clinical research does not support the use of folic acid in patients with CKD when used in combination with high-dose vitamin B12 (cyanocobalamin). Vitamin B12 might increase the risk of negative outcomes (50253,50409,96150). More research is needed to determine the benefits of folic acid when used alone.
• Colorectal cancer. It is unclear if oral folic acid prevents colorectal cancer. Details: Although the majority of population research suggests that taking folic acid orally from dietary and supplemental sources reduces the risk of colorectal cancer (505,2140,2144,2145,2250,6271,9325,9326,50109,50427,50450)(91306,91323,96160,109188,110450), clinical evidence in general is not supportive. Most clinical research and meta-analyses of clinical trials suggest that taking folic acid from dietary or supplemental sources does not reduce the risk of colorectal cancer (2141,34596,50394). The reason for this discrepancy is unclear. Some observational research suggests that an inverse association between folate intake and risk of colorectal cancer was not apparent until at least 12 years after baseline folate intake was determined (109188). A meta-analysis of observational studies suggests that the benefits of folic acid supplementation on colorectal cancer risk might be limited to patients with moderate to high alcohol consumption (110450). Other clinical evidence suggests that the beneficial effect of folic acid may be limited to colon, but not rectal, cancer (21501). Furthermore, the beneficial effect for colon cancer may be limited to only certain subtypes. For instance, females with folate intake of at least 400 mcg daily seem to have a 46% reduction in the risk of p53-overexpressing colon cancer, but not p53-negative tumors, when compared with those who consume less than 200 mcg daily (21300). Also, the source of folic acid may influence its effects. Some observational research suggests that dietary folate, but not folic acid supplementation, reduces the risk of colon cancer (21501).
• Congenital heart disease. It is unclear if oral folic acid prevents congenital heart disease. Details: The exact cause of congenital heart disease is unknown but is thought to be a combination of genetic and environmental factors. Population research has found that supplementation with folic acid or folic acid-containing prenatal vitamins during pregnancy is associated with up to a 40% lower risk of congenital heart defects in newborns (99373).
• Dementia. It is unclear if oral folic acid is beneficial for the prevention or treatment of dementia. Details: While some preliminary research shows that folic acid might aid in the prevention and treatment of Alzheimer disease (13165,15270,50246,90374), two small clinical trials show that taking folic acid 15-20 mg daily for 10-12 weeks does not seem to improve cognitive function or the severity of dementia in patients with various forms of dementia, including vascular dementia, Lewy body dementia, probable Alzheimer disease, or dementia due to other causes (50062,50597).
• Diabetes. Small clinical studies suggest that oral folic acid does not improve glycemic control. Details: Meta-analyses of small clinical trials in patients with type 2 diabetes show that folic acid does not reduce glycated hemoglobin (HbA1C) when compared with placebo (50528,109197). Another small clinical study in patients with diabetes who are stabilized on metformin and/or a sulfonylurea shows that taking folic acid 5 mg daily for 8 weeks does not affect HbA1C when compared with placebo (104917). The validity of this study is limited by its small size and lack of blinding. Conversely, a meta-analysis of clinical research shows that taking folate modestly reduces fasting blood glucose and insulin levels, as well as measures of insulin resistance, when compared with placebo or no intervention (109197). There was no clear relationship between these changes and the dose or duration of folate. However, the studies included in this analysis evaluated multiple patient populations; the effect of folate in patients with diabetes, specifically, is unclear. Beyond glycemic control, some research has assessed the impact of dietary folate intake on cardiovascular risk in patients with diabetes. An observational study in Chinese adults with type 2 diabetes has found that dietary intake of folate in the highest quartile is associated with 68% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with folate intake in the lowest quartile (110452). Folic acid has also been evaluated in gestational diabetes. A meta-analysis of 20 studies shows that serum and red blood cell (RBC) folate levels are higher in patients with gestational diabetes than without gestational diabetes. Subgroup analysis suggests that patients with gestational diabetes have higher serum and RBC folate levels in the second trimester than in those without gestational diabetes, while RBC folate levels in patients with gestational diabetes were higher in the first trimester than those without gestational diabetes. Overall, higher serum folate levels are associated with a slight increase in the odds of gestational diabetes when compared with lower serum folate levels (112107).
• Diabetic neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic neuropathy shows that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate), for 24 weeks does not improve neural dysfunction based on vibration perception, but does seem to improve total neuropathy symptoms, when compared with placebo. These symptoms, which include both sensation and pain, decreased by 25% with the B vitamin combination, compared with only 15% in those taking placebo (90375).
• Epilepsy. It is unclear if oral folic acid reduces seizure frequency. Details: A meta-analysis of preliminary clinical research shows that taking folic acid does not reduce seizure frequency in patients with epilepsy (50124). However, there is some speculation that folate deficiency might be linked to increased seizure frequency. A preliminary clinical study in folate-deficient children with epilepsy shows that taking folic acid 5 mg daily for 3 months reduces seizure frequency when compared to baseline, but not when compared with a control group that is not deficient in folate (99371).
• Erectile dysfunction (ED). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with mild erectile dysfunction, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Esophageal cancer. Higher dietary folate intake is associated with a lower risk of esophageal cancer. Details: One meta-analysis of observational research has found that higher levels of dietary folate are associated with a 34% lower risk of esophageal squamous cell carcinoma and a 50% lower risk of esophageal adenocarcinoma when compared with low levels of dietary folate (50208). Another meta-analysis of observational research has found that consuming high amounts of folate is associated with a 36% decrease in the odds of esophageal cancer when compared with lower dietary folate intake (100950).
• Fenofibrate (Tricor)-induced hyperhomocysteinemia. Folic acid seems to attenuate increases in homocysteine in people taking fenofibrate. Details: A small open-label clinical trial in patients taking fenofibrate shows that adding folic acid 10 mg every other day might reduce elevated plasma homocysteine levels by up to 59% when compared with taking fenofibrate alone (9321).
• Gastric cancer. It is unclear if oral folic acid reduces gastric cancer risk. Details: Observational research has found that taking folic acid reduces the risk of gastric cardia adenocarcinoma by 17% and the risk of noncardia gastric cancer by 33%, but does not reduce the risk of gastric cancer overall (50208). Also, a meta-analysis of 13 small clinical studies in patients with gastric precancerous conditions shows that taking folic acid 20-30 mg daily for 3-6 months improves gastric mucosal atrophy and intestinal metaplasia but does not seem to improve symptoms when compared with a control (110448). Whether these findings are associated with a lower risk of gastric cancer is unclear.
• Gout. It is unclear if oral folic acid reduces the risk for gout. Details: An observational study has found that increased dietary folate intake is associated with a lower incidence of gout (50454).
• Head and neck cancer. It is unclear if oral folic acid is beneficial for head and neck cancer prevention. Details: Population research has found that the highest intake of dietary folate is associated with a 50% reduced risk of head and neck cancer when compared with the lowest intake of folate. Each 100 mcg increase per day seems to reduce the risk by about 4% (96151).
• Hearing loss. It is unclear if oral folic acid prevents hearing loss. Details: Low levels of serum folate seem to be a risk factor for sudden sensorineural hearing loss in adults (21283). Observational research in females has found that serum folate levels in the lowest quintile are associated with a 19% increased risk for hearing loss when compared with levels in the second quintile. Also, folate levels in the highest quintile are associated with a 12% lower risk of hearing loss when compared with the second quintile (109807). A clinical study in older adults from the Netherlands shows that taking folic acid 800 mcg daily for 3 years slows the decline of age-related low-threshold hearing loss when compared with placebo (15163). However, at the time of this study, folate enrichment of foods was not allowed in the Netherlands. As a result, baseline folate levels in this study population were about 50% lower than in the US population. The effect of folic acid supplementation in people with higher baseline folate levels is unclear.
• Infertility. It is unclear if oral 5-methyltetrahydrofolate (5-MTHF) in combination with vitamin B6 and vitamin B12 is more beneficial than folic acid alone for increasing pregnancy rate in females undergoing assisted reproductive technology (ART). Details: Retrospective research from Italy suggests that taking 5-MTHF 400 mcg, vitamin B12 5 mcg, and vitamin B6 3 mg daily results in clinical pregnancy and live birth rates of approximately 60% and 49%, respectively, compared with 45% and 35% of those taking folic acid 400 mcg daily. A sub-analysis suggests that beneficial effects on pregnancy rates are limited to individuals aged less than 40 years (109189). The findings from this study are limited by its retrospective design. Also, it is unclear if these findings are generalizable to countries with folate fortification.
• Kidney failure. It is unclear if oral folic acid is beneficial in patients with kidney failure. Details: Because hemodialysis removes folate from the body, there is concern that folate deficiency may cause complications in patients with kidney failure receiving hemodialysis. Observational research in Taiwanese patients with kidney failure undergoing hemodialysis has found that taking folic acid 5 mg daily for an average of 5.8 years is associated with a 31% lower risk of arteriovenous access thrombosis when compared with folic acid 5 mg weekly. However, daily folic acid supplementation was not linked to a lower risk of cardiovascular events, cancer, or mortality when compared with weekly folic acid (110120). Oral folic acid has also been evaluated in combination with other ingredients. A small, low-quality clinical study in adults with kidney failure undergoing regular hemodialysis shows that taking oral folic acid 30 mg daily with thiamine 90 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if these findings are due to folic acid, thiamine, or the combination.
• Lometrexol toxicity. While oral folic acid might reduce lometrexol toxicity, intravenous folic acid does not seem to help. Details: In a phase I trial, intravenous folic acid 5-25 mg administered 1 hour or 3 hours prior to lometrexol 15-30 mg/m2 every 3 weeks does not seem to reduce cumulative lometrexol toxicity (2161). However, in a phase II study, taking oral folic acid 3 mg/m2 daily in addition to lometrexol 10 mg/m2 weekly seems to attenuate cumulative toxicity and improve its tolerability in cancer patients (104948).
• Low birth weight. It is unclear if oral folic acid supplementation during pregnancy reduces the risk of a low birth weight. Details: Clinical research shows that supplementation with folic acid 200 mcg to 5 mg daily during pregnancy increases mean birth weight when compared with placebo (91307). Furthermore, some population research has found that pre- or peri-conception folic acid supplementation, usually 400 mcg daily, is associated with a reduced risk of a child born small-for-gestational age. However post-conception folic acid supplementation is not associated with reduced risk (91304,103983). An observational study in pregnant Chinese patients found that supplementation with folic acid is associated with a 20% lower odds of low birth weight when compared with no supplementation. This association was observed when folic acid was used both before conception and during pregnancy for at least 24 weeks or during pregnancy only for at least 12 weeks. Increased dietary folate intake was not linked to a lower risk of low-birth-weight infants (110446). However, other observational research has found no association between folic acid supplementation during pregnancy and the risk for small-for-gestational age births (110447).
• Lung cancer. It is unclear if oral folic acid reduces lung cancer risk. Details: There does not appear to be a relationship between deficiency of folate and lung cancer (9454). However, consuming at least 130.4 mcg of folate per 1000 kcal daily seems to reduce the risk of lung cancer by 40% in former smokers when compared to those with lower dietary folate intake (50065).
• Melanoma. It is unclear if oral folic acid reduces melanoma risk. Details: Population research has found that folic acid supplementation of 2-2.5 mg daily in combination with vitamin B6 and vitamin B12 is linked with a 53% reduced risk of melanoma (91312).
• Metabolic syndrome. Although there is interest in using oral folic acid for metabolic syndrome, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Nitrate tolerance. It is unclear if oral folic acid helps to prevent the development of tolerance to treatment with nitroglycerin. Details: Some clinical evidence suggests that taking folic acid 1 mg daily for 1 week does not prevent the development of nitroglycerin-induced endothelial dysfunction or tolerance in healthy individuals (50442). However, other research suggests that taking folic acid 10 mg daily for 1 week prevents nitric oxide synthase dysfunction caused by continuous nitroglycerin (9316).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral folic acid is beneficial for NAFLD. Details: A cross-sectional analysis suggests that adults with NAFLD have lower levels of serum folate and its major component 5-MTHF when compared with healthy controls. Additionally, adults with NAFLD seem to consume less supplementary and dietary folate when compared with healthy controls. Overall, serum folate levels are negatively associated with the risk of NAFLD, and inadequate folate intake is associated with an increased risk of NAFLD (112104).
• Oral clefts. It is unclear if oral folic acid reduces the risk of oral clefts in infants. Details: Observational research has found that maternal folic acid supplementation is associated with an up to 49% reduced risk of cleft lip with or without cleft palate (50220,104921). Furthermore, a large clinical trial in pregnancies at-risk for oral cleft suggests that taking a higher dose of folic acid 4 mg from pre-conception until the end of the first trimester results in a similar oral cleft recurrence rate of 2.5%, compared with a 2.9% recurrence with a lower dose of folic acid (400 mcg). Both doses demonstrate a lower incidence of oral clefts when compared with historical rates of 6.3% (91322). Although there is speculation that genetic markers of folate status impact the effect of folic acid on orofacial cleft incidence, the current data do not show a relationship (104921).
• Overall mortality. It is unclear if oral folic acid reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of folic acid in the highest quintile is associated with a 14% to 23% lower risk of all-cause mortality and a 41% to 47% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary folic acid intake (110451).
• Pancreatic cancer. It is unclear if oral folic acid reduces pancreatic cancer risk. Details: Consuming greater than 280 mcg daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer (9327). A meta-analysis of case-control and cohort studies suggests that consuming higher amounts of dietary folate reduces the risk of pancreatic cancer by 51% compared to low levels of dietary folate (50208). However, another meta-analysis of prospective cohort studies suggests that folate/folic acid intake does not significantly affect the overall risk of pancreatic cancer (50499). The contradictory results may be associated with the form of intake or may be related to the gender of the participants. A meta-analysis of clinical research shows that dietary folate, but not folic acid, significantly reduces the risk of pancreatic cancer (50387). Also, one meta-analysis of observational studies has found that high dietary folate decreases the risk of pancreatic cancer in females, but not males (50387).
• Peripheral neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows taking a combination of folic acid 400 mcg, vitamin B12 3 mcg, and uridine monophosphate 50 mg daily (Keltican) for 60 days reduces pain associated with peripheral neuropathy. Use of this product reduces pain intensity by approximately 44%, with loss of burning pain in approximately 50% of patients, strong tingling or pricking in approximately 57% of patients, strong pain attacks in 92% of patients, and numbness in 90% of patients when compared with baseline. Radiating pain and the use of concomitant medications are also reduced (90384). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to folic acid, other ingredients, or the combination.
• Pharyngeal cancer. It is unclear if oral folic acid reduces pharyngeal cancer risk. Details: Population research has found that intake of folic acid and folate from natural, fortified, and supplemented sources, may protect against oropharyngeal cancer. Intake of at least 258-816 mcg total folate/folic acid reduces the odds by 35% when compared with intakes of less than 344 mcg. Furthermore, folate/folic acid may be more beneficial for oral cancer versus pharyngeal cancer and in heavy alcohol users versus non users or light users (91302).
• Polycystic ovary syndrome (PCOS). It is unclear if oral folic acid is beneficial for PCOS. Details: One clinical study in overweight or obese patients with PCOS shows that taking folate 1 mg or 5 mg daily for 8 weeks modestly reduces levels of homocysteine, as well as insulin resistance, when compared with placebo. However, only the 5 mg dose modestly reduces insulin, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Neither dose appears to affect fasting plasma glucose, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo (109200). Other clinical research in patients with PCOS taking metformin shows that taking folate 400 mcg daily for 6 months does not affect glycemic parameters, plasma lipid levels, or hormone levels when compared with placebo (109194). The reasons for discrepancies between studies are unclear but may relate to patient characteristics. One study included only overweight or obese individuals with at least two of the three PCOS criteria, whereas the other study limited enrollment to patients in any weight category but with all three PCOS criteria (109194,109200).
• Pregnancy-induced hypertension. It is unclear if oral folic acid reduces the risk of hypertension during pregnancy. Details: Population research has found that taking folic acid during pregnancy is not associated with a reduced risk of gestational hypertension (91308,99370,99372).
• Restless legs syndrome (RLS). Although there is interest in using oral folic acid for RLS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Schizophrenia. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of folic acid 2 mg and vitamin B12 400 mcg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral folic acid has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Suicidal ideation. It is unclear if oral folic acid reduces the risk of suicidal ideation or suicide attempts. Details: One observational study has evaluated the association between folic acid supplementation and suicidal events in patients with various underlying conditions, including 12% with depression, 15% with anxiety, and 46% with pain. This within-person cohort study found that filling a prescription for folic acid 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a 44% reduced rate of suicidal events during the months after the prescription when compared with the months without the prescription. For the 48% of patients who received folic acid 1 mg daily, each additional month of taking the prescription was associated with a 5% decrease in suicidal events (109201). Prospective clinical research is needed to confirm any benefits of folic acid and to determine whether baseline folate deficiency plays a role in these outcomes. More evidence is needed to rate folic acid for these uses.

(Read more about FOLIC ACID)

POSSIBLY EFFECTIVE

• Cisplatin-induced neurotoxicity. Intravenous glutathione seems to reduce neurotoxicity from cisplatin. Details: Clinical studies in cancer patients receiving cisplatin shows that administering glutathione 1.5 grams/m2 by intravenous injection over 15 minutes seems to help prevent neurotoxicity and other toxicities from cisplatin when compared with control. Glutathione may also increase the highest dose of cisplatin that patients are able to tolerate (5373,5374,5377,5378,5380). In one study, this same dose of intravenous glutathione was administered, along with intramuscular glutathione 600 mg on days 2-5 (5374).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there is interest in using oral glutathione for aging, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Alcohol use disorder. Although there is interest in using oral glutathione for alcohol use disorder, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Athletic performance. Oral glutathione has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in young, resistance-trained males shows that taking glutathione (Setria, Kyowa Hakko Bio) 200 mg in combination with L-citrulline 2 grams daily for 8 weeks in conjunction with resistance training has no effect on muscle strength, as measured by leg and bench presses, when compared with L-citrulline alone or with placebo (97394). The trial shows the increase in lean body mass with training to be significantly higher with glutathione and L-citrulline compared with placebo at 4 weeks. However, by 8 weeks of training lean body mass is not different between supplementation and placebo. An additional small, cross-over trial in young, endurance-trained males shows that taking glutathione 200 mg in combination with L-citrulline 2 grams (Setria Performance Blend, Kyowa Hakko Bio) daily for 8 days does not improve high speed running performance, as measured by time to exhaustion, when compared with placebo (112285).
• Angioplasty. It is unclear if intravenous glutathione is beneficial in patients recovering from angioplasty following myocardial infarction. Details: A small clinical trial in Italian adults undergoing primary percutaneous coronary intervention (PCI) for recent ST-elevation myocardial infarction (STEMI) shows that intravenous infusion of glutathione sodium salt 2500 mg/25 mL over 10 minutes before angioplasty and at 24, 48 and 72 hours after angioplasty reduces length of hospital stay by around 2 days; reduces markers of oxidative stress, inflammation, and cardiomyocyte damage; and improves measures of left ventricular function at 6-month's follow-up when compared with placebo (111417,111418).
• Alzheimer disease. Although there is interest in using oral glutathione for Alzheimer disease, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Cardiovascular disease (CVD). Although there is interest in using oral glutathione for preventing CVD, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Cataracts. Although there is interest in using oral glutathione for cataracts, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral glutathione for CFS, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Cirrhosis. It is unclear if oral glutathione is beneficial for improving cirrhosis severity. Details: A small clinical study in patients with cirrhosis shows that taking glutathione 500 mg daily with or without vitamin B6 50 mg daily for 12 weeks does not affect disease severity or reduce oxidative stress when compared with placebo (104392). These findings are limited because the study might not have been powered to detect a difference between groups, as 21 of the 61 participants were lost to follow-up.
• Cognitive function. Oral glutathione has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small cross-over trial in healthy adults shows that taking a product providing 20 mg/day of glutathione as part of a combination product containing probiotics (L. helveticus, Lactiplantibacillus plantarum, Bifidobacterium longum), inulin, zinc, potassium, magnesium and lactoferrin (Puraflor, GSK Consumer Healthcare) for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923).
• Contrast induced nephropathy. It is unclear if intravenous glutathione is beneficial for preventing contrast induced nephropathy. Details: A small, non-blinded clinical study in patients aged 65 or older with diabetes undergoing percutaneous coronary intervention (PCI) shows that intravenous reduced glutathione 180 mg daily for 4 days, starting 6 hours prior to PCI, in conjunction with saline hydration, does not reduce the rate of contrast induced nephropathy when compared with saline hydration alone. Saline hydration was administered at a rate of 1 mL/kg/hr, starting 6 hours prior to PCI and continuing for 12 hours after PCI (107477). However, this study may have been inadequately powered to detect a difference between groups.
• Cystic fibrosis. It is unclear if oral glutathione is beneficial in children with this condition. Details: A small clinical study in children ages 2-10 years old with cystic fibrosis shows that taking glutathione powder 65 mg/kg daily in 3 divided doses for 6 months does not impact weight or inflammatory biomarkers when compared with placebo (104391).
• Glaucoma. Although there is interest in using oral glutathione for glaucoma, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Idiopathic interstitial pneumonia. Although there is interest in using inhaled glutathione for idiopathic pulmonary fibrosis, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral glutathione is beneficial in patients with NAFLD. Details: Preliminary clinical research shows that taking glutathione 300 mg daily for 4 months reduces alanine aminotransferase (ALT) levels by around 13% and triglyceride levels by around 16%, but has no impact on aspartate aminotransferase (AST) levels or liver stiffness, when compared with baseline in patients with NAFLD (97397). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there is interest in using oral glutathione for osteoarthritis, there is insufficient reliable information about the clinical effects of glutathione for this condition.
• Parkinson disease. It is unclear if intranasal glutathione is beneficial for improving Parkinson disease symptoms. Details: A small clinical study in patients with Parkinson disease shows that taking glutathione intranasally 100-200 mg three times daily for 3 months has no effect on symptoms when compared with placebo (97398). More evidence is needed to rate glutathione for these uses.

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POSSIBLY EFFECTIVE

• Metabolic syndrome. Oral inositol seems to modestly improve lipid parameters, blood pressure, and insulin resistance in patients with metabolic syndrome. Details: Some clinical research in postmenopausal adults with metabolic syndrome following a low-calorie diet shows that taking myo-inositol 2 grams twice daily for one year reduces total cholesterol by 29 mg/dL, triglycerides by 64 mg/dL, systolic and diastolic blood pressure by 9 mmHg and 6 mmHg, respectively, increases high-density lipoprotein (HDL) cholesterol by 6 mg/dL, and improves insulin resistance when compared with placebo. It did not reduce body mass index or waist circumference in these patients (91554). A meta-analysis of clinical studies in a mixed population shows similar effects on blood pressure, especially among postmenopausal adults with metabolic syndrome, at durations exceeding 8 weeks, and at doses of at least 4 grams (108820). Another clinical study in postmenopausal adults with metabolic syndrome and at risk for breast cancer shows that taking a combination of inositol and alpha-lipoic acid daily for 6 months, in combination with a low-calorie diet, reduces insulin resistance (HOMA-IR) by at least 20% when compared with a low-calorie diet alone. Also, taking inositol and alpha-lipoic acid seems to increase HDL cholesterol by about 6% and reduce triglycerides by 5% when compared to baseline (91543). It is unclear if these effects are due to inositol, alpha-lipoic acid, or the combination.
• Polycystic ovary syndrome (PCOS). Oral inositol, often in combination with folic acid, seems to improve glycemic and lipid parameters, as well as ovulation and pregnancy rates, in some patients with PCOS. Details: Inositol has shown modest benefit on metabolic parameters in patients with PCOS. A meta-analysis of clinical research shows that taking inositol (type not specified) modestly reduces fasting blood glucose, fasting insulin, total cholesterol, triglycerides, and testosterone levels when compared to control (98944). In individual clinical studies, taking D-chiro-inositol 1-1.2 grams or myo-inositol 4 grams with folic acid 400 mcg daily for 6 months decreases serum triglyceride and testosterone levels, modestly decreases blood pressure, and improves ovarian function (2028,91552). An unblinded clinical study shows that taking metformin with a combination of myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily is associated with improved lipid parameters and postprandial insulin levels at 6 months when compared with metformin alone (108822). It is unclear if the improvement from baseline differed between groups. Other research shows that taking myo-inositol and D-chiro-inositol together may improve metabolic parameters faster than taking myo-inositol alone (91550). Myo-inositol has also been compared with metformin in some clinical research, with some evidence of benefit (95085,95086). Meta-analyses of small clinical studies shows that taking myo-inositol 2-4 grams daily, with or without folic acid, for 12-24 weeks does not improve fasting insulin, insulin resistance (HOMA-IR), androgen levels, body mass index (BMI), or waist-hip ratio when compared with metformin 1.5-2.5 grams daily, although it seems to have a lower risk of adverse effects (100705,108823). These analyses are limited due to the small size, methodological issues, and high heterogeneity of the included studies. Other research has evaluated the effects of inositol on ovulation and pregnancy outcomes. Some research suggests that inositol increases ovulation rate in patients with PCOS (98944). A small clinical study shows that taking myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li.Pharma) daily for three spontaneous cycles induces ovulation in about 62% of individuals with anovulatory PCOS and insulin resistance. Adding clomiphene citrate with myo-inositol induces ovulation in about 72% of the patients who remain anovulatory after treatment with myo-inositol alone (91547). Another clinical study shows that taking a combination of inositol 2 grams, folic acid 200 mcg, and N-acetyl cysteine 600 mg (Ovaric HP, Just Pharma) twice daily for 12 months improves ovulation rates in PCOS patients with oligomenorrhea, regardless of insulin sensitivity at baseline (91553). Some research has also investigated the effects of taking both isomers of inositol concomitantly. Taking myo-inositol 550 mg plus D-chiro-inositol 13.8 mg (Inofolic Combi, Lo.Li.Pharma) twice daily, beginning 12 weeks before ovarian hyperstimulation and continuing throughout pregnancy, improves oocyte quality when compared to treatment with D-chiro-inositol alone. The combination appears to increase fertilization rate in patients aged 35 years or younger, but not those older than 35 years (91544). Other clinical research shows that taking myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily for 12 weeks improves pregnancy rates and live birth rates by an additional 10% and 11%, respectively, when compared with myo-inositol 550 mg plus D-chiro-inositol 13.8 mg. The higher-dose combination also resulted in a 15% lower rate of ovarian hyperstimulation syndrome when compared with those taking the lower dose of D-chiro-inositol (102317). Research has also evaluated the effects of inositol on other pertinent clinical outcomes in PCOS. Several small clinical studies show that taking the combination of myo-inositol and D-chiro-inositol, alone or in combination with metformin, improves menstrual cycle irregularity when compared with metformin alone, but not as much as a taking a combined hormonal contraceptive (108822,108824). The validity of these findings is limited by the unblinded nature of the studies. Also, a small clinical study shows that taking metformin with myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily is associated with improved acne, but not hirsutism, at 6 months, when compared with metformin alone (108822). It is unclear if the improvement from baseline differed between groups. The validity of these findings is limited by the unblinded nature of the study.
• Preterm labor. Oral inositol in combination with folic acid seems to prevent preterm labor in individuals at risk for gestational diabetes. Details: A meta-analysis of five clinical trials in individuals at risk for gestational diabetes shows that taking myo-inositol plus folic acid daily, beginning during the first trimester and continuing throughout pregnancy, decreases the risk of preterm delivery by 64% when compared with folic acid alone. Patients in all but one study included in this analysis took myo-inositol 2 grams plus folic acid 200 mcg twice daily, while patients in the other study took myo-inositol 1100 mg plus D-chiro-inositol 27.6 mg and folic acid 400 mcg daily (100706). It's unclear if these results are generalizable to individuals with a low risk for gestational diabetes.

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral D-chiro-inositol is beneficial in patients with age-related testosterone deficiency. Details: A very small clinical study in males aged 65-75 years with low-normal morning testosterone levels and signs and symptoms of androgen deficiency shows that taking D-chiro-inositol 600 mg twice daily for 30 days improves sexual function and physical strength when compared with baseline (108821). The validity of these findings is limited by the lack of a comparator group.
• Bipolar disorder. It is unclear if oral inositol is beneficial in patients with bipolar disorder. Details: Preliminary clinical research in children aged 5-12 with bipolar disorder shows that taking a combination of inositol 80 mg/kg (maximum 2 grams) and eicosapentaenoic acid (EPA; Nordic Naturals) 3 grams daily for 12 weeks moderately reduces manic and depressive symptoms as well as symptoms of anxiety and oppositional defiant disorder. This improvement is greater than what is seen when either ingredient is taken alone (95092).
• Chemotherapy-induced leukopenia. Oral inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults undergoing breast cancer surgery and adjuvant chemotherapy shows that taking inositol orally 390 mg twice daily and applying IP-6 gel 4% twice daily to the surgical site, starting 2 weeks before adjuvant chemotherapy and stopping 2 weeks after the last cycle, attenuates reductions in white and red blood cell counts when compared with no intervention. Using inositol and IP-6 also improves breast and arm symptom scores and some quality of life scores; however, these improvements were not consistent over time.
• Diabetes. It is unclear if oral inositol is beneficial for the treatment of type 1 diabetes or the prevention of gestational diabetes. Details: Preliminary clinical research in patients with type 1 diabetes and a body mass index of at least 25 kg/m2 shows that taking a specific combination product containing D-chiro-inositol and folic acid (Chirofol 500, LJ Pharma) daily for 6 months, along with insulin therapy, decreases glycated hemoglobin (HbA1c) by approximately 0.5% when compared to taking folic acid alone with insulin therapy. However, there was no difference between groups with respect to insulin resistance or body mass index (95088). Most research shows that taking inositol during pregnancy prevents gestational diabetes. However, most studies conducted to date are of low quality and it is unclear if the results are generalizable. Most clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg twice daily (usually as Inofolic, Lo.Li. Pharma International), beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of gestational diabetes by 57% to 92% when compared with folic acid alone in patients at risk for gestational diabetes. Myo-inositol seems to be more effective than D-chiro-inositol (91545,91548,95083,95084,100706,103750,104688). However, supplementation with lower doses of inositol, mimicking natural inositol occurring in the body, may not be effective. One clinical study shows that taking a combination of myo-inositol 1.1 grams, D-chiro-inositol 27.6 mg, and folic acid 400 mcg (Inofolic Combi, Lo.Li. Pharma International) daily during pregnancy does not decrease the incidence of gestational diabetes when compared with folic acid alone in patients with a family history of diabetes (95082,103750). In patients eventually diagnosed with gestational diabetes, one small clinical study shows that taking myo-inositol 2 grams reduces the number of patients requiring insulin by at least 50% (104688), although another small clinical study shows that adding D-chiro-inositol, myo-inositol, or both to folic acid does not affect insulin resistance when compared with placebo (98945).
• Dyslipidemia. Although there has been interest in using oral inositol for hypercholesterolemia and hypertriglyceridemia, there is insufficient reliable information about the clinical effects of inositol for these conditions.
• Hypertension. Although there has been interest in using oral inositol for hypertension, there is insufficient reliable information about the clinical effects of inositol for this condition.
• Infertility. It is unclear if oral inositol is beneficial in patients undergoing intracytoplasmic sperm injection (ICSI). Details: Several small studies in patients undergoing ICSI show that taking a specific combination product containing myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li. Pharma International S.r.l) by mouth daily, starting 1-3 months before ICSI and continuing until ovulation, improves fertilization rate, but does not improve implantation or pregnancy rates, when compared with taking folic acid alone (103752,108825).
• Insomnia. It is unclear if oral inositol is beneficial for improving sleep during pregnancy. Details: Clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) before bed for 10 weeks, starting at 14 weeks gestation, improves overall measures of sleep quality by a small amount when compared with folic acid alone. However, this improvement was not maintained until 37-38 weeks' gestation. Also, the study was not limited to patients with poor sleep quality during pregnancy, but to any healthy pregnant individual (104687).
• Lithium-induced side effects. It is unclear if oral inositol is beneficial for reducing lithium-induced side effects. Details: A small clinical study suggests that taking inositol 6 grams daily for 10 weeks may improve psoriasis associated with lithium therapy when compared with baseline (11972). However, taking inositol orally does not seem to improve other lithium-induced adverse effects, such as tremor, thirst, and changes in thyroid and adrenal function (2027).
• Lung cancer. It is unclear if oral inositol is beneficial for slowing the rate of bronchial dysplasia. Details: Preliminary clinical research in smokers with bronchial dysplasia considered at high risk for lung cancer shows that taking myo-inositol (Tsuno Food Industries Co., Ltd.) 9 grams orally once daily for 2 weeks then twice daily for 6 months, does not increase the rate of complete or partial response when compared with placebo (95090).
• Obsessive-compulsive disorder (OCD). It is unclear if oral inositol is beneficial in patients with OCD. Details: One preliminary clinical study in adults with OCD shows that taking inositol 18 grams daily for 6 weeks improves Yale-Brown Obsessive Compulsive Scale scores when compared with placebo (2186). However, taking inositol does not seem to improve the severity or type of OCD symptoms in patients already taking a selective serotonin reuptake inhibitor (91556). Both of these studies were small, and treatment was administered for only 6 weeks.
• Panic disorder. Oral inositol seems to improve symptoms of panic disorder. Details: A very small clinical study shows that taking inositol 12 grams daily reduces the severity and rate of panic attacks and the severity of agoraphobia over 4 weeks of treatment when compared with placebo (2184). Another very small clinical study shows that taking inositol 18 grams daily for one month may be as effective as fluvoxamine 150 mg daily for treatment of panic disorder (10387). However, the one-month duration may not have provided adequate time to see the full effects of fluvoxamine.
• Post-traumatic stress disorder (PTSD). It is unclear if oral inositol is beneficial in patients with PTSD. Details: Preliminary clinical research shows that taking inositol 12 grams daily for 4 weeks does not improve distress when compared with placebo in patients with PTSD (91557).
• Pregnancy-induced hypertension. It is unclear if oral inositol is beneficial for preventing hypertension during pregnancy. Details: In patients with a body mass index (BMI) between 25-29.9 kg/m2, preliminary clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) twice daily, beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of pregnancy-induced hypertension by 66% when compared with folic acid alone (104688).
• Psoriasis. It is unclear if oral or topical inositol is beneficial for improving symptoms of psoriasis. Details: One small clinical study shows that taking inositol 6 grams daily for 10 weeks does not improve symptoms of psoriasis in a small group of patients when compared to baseline. However, taking this dose of inositol has a moderate effect on overall symptoms in patients with psoriasis related to lithium use (11972). Preliminary clinical research also shows that topical use of D-chiro-inositol is unlikely to be beneficial for reducing overall symptoms of psoriasis. Topical application of inositol 0.25% or 1% for 6 weeks improves overall symptoms when compared with baseline. However, the inositol-containing creams were no more effective than the control cream (104686).
• Trichotillomania. It is unclear if oral inositol is beneficial for reducing hair pulling. Details: Preliminary clinical research shows that taking inositol in doses ranging from 6-18 grams daily over a period of 10 weeks is no more effective than placebo in reducing subjective or clinician-documented symptoms of hair pulling in patients with trichotillomania (95089). More evidence is needed to rate inositol for these uses.

(Read more about INOSITOL)

LIKELY EFFECTIVE

• Iodine deficiency. Oral iodine supplements, including iodized salt, are effective for improving iodine status and reducing goiter size in adults and children. Iodine supplementation is also recommended during pregnancy in areas at risk for iodine deficiency. Details: Iodine deficiency is associated with several adverse outcomes. The earliest clinical symptom of iodine deficiency is low circulating thyroid hormone and thyroid stimulating hormone (TSH), followed by thyroid goiter (7135,16747,91398). Iodine deficiency and subsequent hypothyroidism can lead to anovulation, infertility, autoimmune thyroiditis, and gestational hypertension. Iodine deficiency is also associated with increased risk of thyroid cancer (16747). Clinical research shows that taking iodine supplements, including iodized salt, improves iodine status and reduces goiter size in adults with iodine deficiency (16747,55919,103071). Studies also show that taking iodine supplementation, including iodized salt, in areas of endemic iodine deficiency, reduces goiter size in children (16747,55919). When taken during pregnancy for iodine deficiency, iodine supplements and iodized salt reduce both maternal and newborn thyroid size and thyroglobulin; however, the effect on maternal TSH is inconsistent (91399,103070). Although some clinical studies and one analysis show that perinatal use of iodine has no effect on the incidence of thyroid disorders during pregnancy (91399,97240,97241), one analysis shows that iodine supplementation reduces the risk of postpartum hyperthyroidism by 68% when compared with placebo (97240). Taking iodine supplementation before 12 weeks' gestation appears to be more effective than when taken later in pregnancy. Perinatal iodine supplementation has no effect on preterm birth rate (97240,97241). Evidence is limited to females with mild-moderate iodine deficiency; the routine use of iodine supplementation during pregnancy has not been extensively studied. For example, the effect of perinatal supplementation on newborn neurocognitive development is conflicting and the evidence is generally low quality (55976,97241,105880,108706). Despite the limited evidence, iodine supplementation is recommended in areas at risk of deficiency.
• Radiation exposure. Oral potassium iodide prevents thyroid uptake of radioactive iodine. However, it does not protect against other sources of radiation. Details: Taking potassium iodide is effective for preventing the uptake of radioactive iodine by the thyroid (7517,7518). Doses of potassium iodide protect for about 24 hours. Therefore, it should be taken daily until the risk of radiation exposure no longer exists (17575,17576).

POSSIBLY EFFECTIVE

• Conjunctivitis. Ophthalmic povidone-iodine solution seems to reduce the risk of conjunctivitis in infants. It may also improve the resolution of acute conjunctivitis in adults. It is unclear if it is beneficial in patients with adenoviral conjunctivitis. Details: A meta-analysis of low-quality clinical trials shows that povidone-iodine solutions are more effective than silver nitrate for preventing neonatal conjunctivitis. However, povidone-iodine solutions are not more effective than erythromycin or chloramphenicol (56084). Povidone-iodine in combination with dexamethasone also seems to be helpful in adults. A clinical trial in patients with acute viral conjunctivitis shows that applying povidone-iodine 0.6% with dexamethasone 0.1% four times daily for 4 days improves clinical symptoms and eradiation of viral counts when compared with placebo control (103075). A small clinical study in adults with adenoviral conjunctivitis shows that administering 4-5 drops of a povidone-iodine 5% eye drop solution within 4 days of symptom onset decreases viral load, mucoid discharge, and bulbar edema and redness on day 4 of a 21-day follow-up period, but at no other time points, when compared with a single dose of artificial tears (108705). Due to the single-dose nature of this study, the effects of continued administration are unclear.
• Diabetic foot ulcers. Topical iodine seems to help with the management of diabetic foot ulcer wounds. Details: A small clinical study in patients with diabetic foot ulcers shows that topically applying cadexomer iodine ointment (Iodosorb) for 12 weeks seems to improve healing to a similar degree as using standard treatment with gentamicin solution, streptokinase, and/or dry saline gauze (2200).
• Endometritis. Topical application of iodine prior to cesarean delivery seems to reduce the risk of endometritis. Details: A meta-analysis of eight clinical trials shows that vaginally applying povidone-iodine 1% to 10% solution immediately before cesarean delivery reduces the risk of post-cesarean endometritis by 62% when compared with saline or no cleaning. It also reduces postoperative fever by 13% and wound infection by 23% (99794). These findings are consistent with other meta-analyses (56080,103076). There seems to be no difference in benefit whether povidone-iodine 1%, 5%, or 10% is used. A network meta-analysis of clinical studies in patients having cesarean delivery suggests that povidone-iodine is no better at preventing endometritis than using chlorhexidine or metronidazole; however, there may not have been sufficient power to detect a difference (103076).
• Fibrocystic breast disease. Oral iodine seems to reduce breast pain in patients with fibrocystic breast disease. Details: Preliminary clinical research in patients with fibrocystic breast disease shows that taking sodium iodide, protein bound iodide, or molecular iodine for 6 months or longer improves mastalgia and reduces breast nodules when compared with baseline or control. Molecular iodine in doses of 70-90 mcg/kg appears to be more effective and better tolerated than the other forms (2197). Another clinical study in patients with cyclic mastalgia due to fibrocystic breast disease shows that taking tablets containing molecular iodine 3000-6000 mcg daily for 5 months reduces pain, tenderness, and nodularity in patients with cyclic mastalgia when compared with placebo. However, a lower dose of 1500 mcg daily does not appear to be beneficial (55960).
• Oral mucositis. Rinsing the mouth with a povidone-iodine solution may prevent oral mucositis from radiochemotherapy. Details: Small clinical studies in patients receiving radiation and chemotherapy for cancer shows that using an oral povidone-iodine rinse seems to reduce the risk for oral mucositis when compared with using sterile water (2198,2199).
• Periodontitis. Rinsing with povidone-iodine solution in addition to scaling and root planing seems to be modestly beneficial in patients with periodontitis. Details: A meta-analysis of mostly small clinical studies in patients with chronic periodontitis suggests that rinsing with povidone-iodine 0.1% to 10% during scaling and root planing modestly reduces the periodontal pocket depth when compared with rinsing with water or saline solution (56072).
• Postoperative infection. Povidone-iodine antisepsis prevents postoperative infection when compared with inactive controls such as normal saline and water. However, it is unclear how it compares to active controls such as chlorhexidine; practice guidelines are conflicting. Details: A meta-analysis of clinical research shows that intraoperative application of povidone-iodine reduces the risk of surgical site infection by approximately 40% when compared with saline or no irrigation (56088). However, research comparing povidone-iodine with other antiseptics such as chlorhexidine is conflicting, as are official guidelines for surgical antisepsis. Many of these discrepancies seem to be related to the presence or absence of alcohol in the preparation. A meta-analysis of clinical research comparing aqueous or alcohol-based povidone-iodine shows that using alcohol-based chlorhexidine for skin antisepsis is more effective for preventing postoperative surgical site infections and may be associated with a lower overall positive culture rate. However, since evidence for both aqueous and alcohol-based solutions of povidone-iodine were included in this study, it is unclear if this may have affected outcomes (108710). The National Institute for Health and Care Excellence (NICE) Guideline recommends chlorhexidine solution as the first choice for preparing the skin for surgery, with povidone-iodine solution as a second-line option. The antiseptic solutions are recommended to be alcohol-based as long as the surgical site is not near a mucous membrane (105906). The World Health Organization (WHO) guidelines also recommend alcohol-based chlorhexidine solutions over either alcohol-based or aqueous povidone-iodine for preventing surgical site infections. However, some experts have expressed concern that these recommendations are based on faulty evidence, as some studies used povidone-iodine preparations with lower alcohol amounts than their comparator groups (105898). In fact, the guideline from the Centers for Disease Control and Prevention (CDC) does not differentiate between povidone-iodine and chlorhexidine antiseptic solutions as long as they are alcohol-based (105905).
• Thyroid storm. Oral iodine is recommended as an adjunct to standard treatment for thyroid storm. Details: The American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) recommend a multimodality approach for treating thyroid storm that includes taking five drops of a saturated solution of potassium iodine every 6 hours (15,92699).
• Thyroid nodules. Combining oral iodine with thyroxine seems to improve the resolution of thyroid nodules. Details: A clinical study in patients with benign nodular thyroid disease and possible iodine deficiency shows that taking iodized salt 200 mcg daily in addition to thyroxine 1.5 mcg/kg daily after surgery seems to reduce the size of the thyroid remnant by 40%, compared with a 10% reduction in patients given thyroxine alone (55927). Also, one large clinical trial in patients with nodular goiter shows that taking potassium iodide 150 mcg daily in combination with levothyroxine 50-100 mcg daily for 12 months reduces nodule volume by about 17%, compared with 7% in the group using levothyroxine alone (91392).
• Venous leg ulcers. Topical cadexomer iodine seems to improve the healing of venous leg ulcers; however, it is unclear if applying povidone-iodine is beneficial. Details: A meta-analysis of four small clinical studies in patients with venous leg ulcers shows that applying cadexomer iodine results in complete healing of ulcers in 33% of patients after 4-12 weeks, compared with only 15% of patients receiving standard care alone. However, use of cadexomer iodine was associated with more adverse effects than standard care. Furthermore, preliminary clinical research shows that applying cadexomer iodine is comparable to hydrocolloid dressing, paraffin gauze dressing, dextranomer, and silver-impregnated dressings for improving the rate of complete healing. A meta-analysis of preliminary clinical research show that povidone-iodine has comparable healing rates when compared with amoxicillin, hydrocolloid dressings, and moist or foam dressings (99798). These findings were consistent with an older version of this meta-analysis (56076).

POSSIBLY INEFFECTIVE

• Catheter-related infections. Topical povidone-iodine seems to be less effective than chlorhexidine for preventing infections from intravascular catheters. Furthermore, it does not seem to reduce the risk of catheter-related urinary tract infections. Details: One meta-analysis of clinical research shows that topical application of povidone-iodine reduces the risk of bloodstream infections when applied at the insertion site of hemodialysis central venous catheters (55883). However, disinfecting catheter insertion sites using povidone-iodine seems to be less effective for preventing blood stream infections in patients receiving central venous, pulmonary artery, or peripheral artery catheters when compared with chlorhexidine solutions (55883,55916). In addition, periurethral cleansing with povidone-iodine 10% prior to bladder catheterization, as well as bladder irrigation with povidone-iodine 2% prior to urinary catheter removal, does not seem to reduce the risk of urinary tract infections when compared with placebo (56058,56126).
• Prematurity. Maternal iodine supplementation does not seem to impact neurological development in premature infants. Details: A meta-analysis of two clinical trials in premature infants shows that adding iodine to enteral or parenteral feeds does not improve mental, visual, or auditory development or reduce the risk of death when compared with no iodine supplementation (99797).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Chyluria. It is unclear if topical iodine is beneficial in patients with chyluria. Details: A small clinical study in patients with chyluria suggests that using povidone-iodine 0.2% solution as a sclerosant in renal pelvic instillation sclerotherapy (RPIS) may be as effective as using silver nitrate 1% (55970).
• Corneal ulceration. It is unclear if topical iodine is beneficial in patients with corneal ulceration. Details: Preliminary clinical research shows that administering povidone-iodine 2.5% eye drops every two hours for two weeks in addition to standard antibiotic therapy does not reduce visual impairment in patients with corneal ulcers when compared with standard antibiotic therapy alone (55971).
• Coronavirus disease 2019 (COVID-19). It is unclear if rinsing with a povidone-iodine mouthwash and using a povidone-iodine nasal spray and ointment can reduce the spread of COVID-19. Details: A small clinical study in adults with PCR-confirmed COVID-19 shows that orally swishing and gargling 25 mL of povidone-iodine (PI) 1% solution, then, into each nostril, spraying 2.5 mL of PI 1% solution and applying one dab of PI 10% ointment, and repeating this 4 times daily for 5 days does not seem to alter the quantity of viral RNA over time when compared with control (105877). The validity of this finding is limited because all study participants achieved negative viral titers on the third day of the study.
• Cutaneous sporotrichosis. It is unclear if topical iodine is beneficial in patients with cutaneous sporotrichosis; research is conflicting. Details: Anecdotal reports and case series suggest that taking saturated solution of potassium iodide (SSKI) orally is effective for most patients when used alone or in combination with another antifungal, including terbinafine or itraconazole (17562,17563,17564,17565,17566,17567,17568,17569,17570,17571) (17572,17573). In one non-controlled clinical study, treatment with SSKI, starting with 3 drops (150 mg potassium iodide) daily and titrating up, resulted in symptom resolution in about 90% of patients after about 33 days of treatment (17561). However, some patients are not able to take SSKI due to intolerable side effects (17561,17572).
• Hyperthyroidism. It is unclear if oral potassium iodide is beneficial for patients with Graves' disease undergoing total thyroidectomy. Details: A retrospective study in patients with Graves' disease undergoing total thyroidectomy shows that preoperative administration of saturated solution of potassium iodide (SSKI) 5% does not reduce the rate of postoperative complications, such as transient or permanent hypoparathyroidism, transient recurrent laryngeal nerve (RLN) palsy, definitive RLN palsy, and cervical hematoma, when compared with no preoperative administration (108707).
• Infant development. It is unclear if maternal iodine supplementation impacts neurological development in infants. Details: Three-year follow-up data from a clinical study in infants and breastfeeding females shows that maternal supplementation of iodine 150 mcg daily improves child cognitive scores, but does not affect language or motor scores, when compared with placebo. Supplementation with a higher dose of 300 mcg daily yielded similar cognitive, language, and motor scores as the 150 mcg dose (108706). This finding aligns with the daily recommended dietary allowance (RDA) of 290 mcg during lactation, which is sometimes achieved by augmenting the diet with a 150-mcg iodine supplement (7135).
• Postoperative bleeding. It is unclear if topical iodine is beneficial in patients with postoperative bleeding. Details: A small clinical study suggests that irrigating extraction sockets with povidone-iodine 1% stops bleeding in a greater number of patients following tooth extraction when compared with a saline solution (56011).
• Rhinosinusitis. It is unclear if topical iodine is beneficial in patients with rhinosinusitis. Details: A small prospective cohort study in patients with recalcitrant chronic rhinosinusitis has found that using a povidone-iodine 0.08% nasal rinse every other day for 7 weeks in addition to standard therapy improves symptoms and reduces signs of infection when compared with baseline (103074). However, one small clinical study in patients with a history of sinus surgery and acute exacerbations of chronic sinusitis shows that receiving povidone-iodine nasal irrigations twice daily for 30 days is no different than irrigations with mupirocin or normal saline for improving nasal symptoms. However, mupirocin tended to reduce bacteria count to a greater extent than the povidone-iodine solution (105878). This finding is limited due to small study size and potential lack of power to detect differences between groups.
• Thyroid cancer. It is unclear if dietary iodine is associated with complications in patients with papillary thyroid cancer. Details: A retrospective study in patients in China with papillary thyroid cancer has found that dietary intake of iodine resulting in serum concentrations greater than 90 mcg/L is associated with a 75% increased risk of cervical lymph node metastases when compared with concentrations less than 45 mcg/L (108708). Actual dietary intake of iodine was not reported, limiting the validity of this finding.
• Ventilator-associated pneumonia (VAP). It is unclear if oral iodine rinse is beneficial for the prevention of VAP. Details: A small clinical study in patients with severe head trauma suggests that regularly rinsing the throat with 20 mL of povidone-iodine 10% solution decreases the risk for VAP when compared with using a saline rinse (56003).
• Wound healing. It is unclear if topical iodine is beneficial for wound healing. Details: A meta-analysis of clinical research shows that topical iodine, as cadexomer iodine or povidone-iodine, is superior to non-antiseptic dressings and some antiseptic agents, such as silver sulfadiazine, for reducing wound size. However, iodine seems to be less effective than local antibiotics such as rifamycin (56083). More evidence is needed to rate iodine for these uses.

(Read more about IODINE)

POSSIBLY EFFECTIVE

• Age-related macular degeneration (AMD). When used alone or in combination with other ingredients, oral lutein seems to improve some aspects of vision in patient with AMD. However, it does not seem to slow the progression of AMD. Details: Epidemiological research has found that people who consume higher amounts of lutein plus zeaxanthin in the diet have a reduced risk of developing AMD (219,2394,60238,106353). The association between intake of lutein specifically and the development of AMD is not clear; however, dietary lutein levels are much higher than dietary zeaxanthin levels. Although one study found no association between increased dietary lutein consumption and a reduced risk for age-related maculopathy, people in this study already had high lutein intake at baseline (14007). Some research has assessed whether lutein supplements can reduce symptoms and progression of existing AMD. Clinical research, including pooled analyses, in adults with AMD shows that taking supplemental lutein 10-20 mg daily for up to 36 months modestly improves some aspects of vision, such as macular pigment optical density, the ability of the eyes to adapt to varying light conditions (glare recovery), the ability to see details of near objects (near vision acuity), and the ability to see under low-contrast conditions (contrast sensitivity) (11798,48213,60185,60242,60245,60268,60270,60280,90678,91160)(91165,97225,102887,106366). Meta-analyses of these and other studies shows that taking lutein or a related xanthophyll carotenoid (zeaxanthin or meso-zeaxanthin) improves macular optical density when compared with placebo in patients with or without AMD. Treatment duration of at least 3 months, doses greater than 5 mg, and/or combination treatment with all three carotenoids are associated with a greater improvement in macular optical density (97225,106366). However, lutein supplements do not appear to affect the progression of AMD (60281). A meta-analysis of 6 studies shows that taking lutein supplements for 0.5-5 years does not reduce the risk of visual loss or progression to late-stage AMD when compared with placebo (95839). Lutein has also been evaluated in combination with other ingredients, with conflicting findings. Although not all research agrees, lutein-containing combination supplements might improve some symptoms of AMD (19196,60134,60180,60207,60237,60244,97226). A specific supplement (AZYR SIFI) containing lutein 10 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 22.5 mg, copper 1 mg, zeaxanthin 1 mg, and astaxanthin 4 mg has been used daily for 1-2 years in some research with moderate evidence of benefit (19196,60244). Taking lutein 10 mg plus zeaxanthin 2 mg in addition to the original Age-Related Eye Disease Study (AREDS) formulation (vitamins C and E, beta carotene, and zinc) does not seem to prevent the progression to advanced AMD more than the AREDS formulation alone. However, this progression was modestly inhibited in individuals with low dietary intakes of lutein and zeaxanthin. While progression to late AMD was only modestly inhibited at 5 years when these doses of lutein and zeaxanthin were included in a revised formulation devoid of beta-carotene (AREDS2) (60281), results of an additional 5 years of follow up showed that this revised formulation reduces the risk of progression to late AMD by 15% when compared with the formulation containing beta-carotene (108615). In first-generation offspring of parents with neovascular AMD, taking lutein 10 mg, zeaxanthin 2 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 15 mg, and copper 1 mg daily for 6 months does not improve the macular pigment optical density (106347). Reasons for these discrepancies are not clear but may relate to lutein dose, dietary lutein intake, treatment duration, or the other ingredients included in the combination products.
• Cataracts. Increased dietary lutein seems to reduce the odds of developing cataracts. It is unclear if oral lutein supplementation is beneficial in those who already have cataracts. Details: Observational research and a meta-analysis of this evidence suggests that higher blood levels and/or higher dietary intake of lutein are associated with a 25% lower odds of developing age-related cataracts, and more specifically, a 25% to 27% decreased risk of developing nuclear cataracts (90944,91161,91162,112095). Population research has also found that people who consume higher amounts of lutein (6.9-11.7 mg daily) as part of their diet have a reduced risk of developing severe cataracts that require surgical removal (2395,3219,3220). Clinical research shows that taking lutein 10 mg and zeaxanthin 2 mg per day orally for an average of 4.7 years decreases the risk of needing cataract surgery by 32% in patients with low dietary intake of lutein and zeaxanthin; however, it doesn't benefit patients with higher dietary intake of lutein and zeaxanthin (94703). Some evidence shows that supplemental lutein might benefit patients who already have cataracts. Preliminary clinical research in adults with grade 2 or 3 senile cataracts shows that taking lutein 15 mg orally three times weekly for up to 2 years can improve the ability to see clearly when compared to baseline (60133).

POSSIBLY INEFFECTIVE

• Bronchopulmonary dysplasia. Oral lutein does not seem to prevent bronchopulmonary dysplasia in preterm and low birth weight infants. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing lutein 0.14 mg and zeaxanthin 0.0006 mg orally once daily, starting at birth and continuing until 36 weeks corrected gestational age, does not decrease the incidence of bronchopulmonary dysplasia when compared with placebo (91163).
• Necrotizing enterocolitis (NEC). Oral lutein does not seem to prevent NEC in preterm and low birth weight infants. Details: Clinical research shows that giving preterm and low birth weight infants a specific product (LUTEINofta, SOOFT Italia SpA) containing lutein 0.14 mg and zeaxanthin 0.0006 mg orally once daily, starting at birth and continuing until 36 weeks corrected gestational age, does not decrease the incidence of NEC when compared with placebo (91163).
• Retinitis pigmentosa. Oral lutein does not seem to improve vision or slow down retinal degeneration in patients with this condition. Details: While some preliminary clinical evidence suggests that oral lutein might be helpful in the treatment of retinitis pigmentosa (10279), most clinical research shows that taking lutein does not improve vision or other markers of retinal degeneration in patients with retinitis pigmentosa (60117,60165,60225).
• Retinopathy of prematurity. Oral lutein does not seem to prevent retinopathy of prematurity in preterm and low birth weight infants. Details: Clinical research in preterm and low birth weight infants shows that giving 0.5 mL or 1.8 mL/kg of a specific product (LUTEINofta, SOOFT Italia SpA) providing lutein 0.14 mg, or giving 0.5 mg/kg plus zeaxanthin 0.0006 mg or 0.02 mg/kg orally once daily, starting at birth and continuing until 36-40 weeks corrected gestational age, does not decrease the incidence or severity of retinopathy of prematurity when compared with placebo (60240,60243,91163,102889).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral lutein is beneficial for attenuating cognitive decline in older adults. Details: Clinical research in adults 40-75 years old shows that taking lutein 10 mg with zeaxanthin 2 mg daily for 6 months improves some, but not all, measures of visual memory when compared with placebo. However, other measures of memory and cognitive function were not improved (109763). Preliminary clinical research in older adults shows that taking the same dose of lutein and zeaxanthin for one year modestly improves some measures of cognitive function, such as complex attention and cognitive flexibility, when compared with placebo (106367). Other preliminary clinical research in older females shows that taking lutein 12 mg alone or with docosahexaenoic acid (DHA) 800 mg daily for 4 months can improve verbal fluency and memory scores when compared to baseline (48216). Also, some observational research in patients 50 years and older has found that higher dietary lutein and zeaxanthin intake is associated with greater word recall when compared with lower intake (102891). However, clinical research in patients over 60 years old shows that taking lutein 10 mg with zeaxanthin 2 mg daily for 5 years in addition to vitamins C and E, beta-carotene, and zinc (AREDS) does not improve markers of cognitive function, such as memory and verbal fluency, when compared with AREDS alone (94702). More research is needed to determine whether lutein is beneficial for specific measures of cognitive function in older adults.
• Alzheimer disease. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 mg), and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of lutein alone is unclear.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral lutein is beneficial for ALS prevention. Details: Population research has found that higher dietary intake of lutein is associated with a 21% lower risk of developing ALS when compared with lower dietary intake (90412). It is unknown if supplemental lutein has any effect on the risk of developing ALS.
• Asthenopia (eye strain). It is unclear if oral lutein is beneficial for eye strain. Details: Preliminary clinical research shows that some combination lutein supplements might reduce symptoms of eye strain. Results from one clinical trial show that taking a combination product containing lutein, zeaxanthin, and black currant extract daily for 2 weeks improves visual fatigue and eye stress when compared with placebo in patients completing a two-hour visual proof reading task (60214). Other clinical research shows that taking lutein 17.5 mg plus omega-3 fatty acids (standardized to contain docosahexaenoic acid 783 mg and eicosapentaenoic acid 162 mg) and bilberry extract (standardized to contain anthocyanidin 59 mg) daily for 4 weeks reduces symptoms of eye strain when compared with placebo (35470). The effect of lutein alone on eye strain is unclear.
• Asthma. It is unclear if oral lutein is beneficial for asthma prevention. Details: Population research has found that a higher dietary intake of lutein plus zeaxanthin is associated with up to 30% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of lutein intake alone or lutein supplementation are unclear.
• Cardiovascular disease (CVD). Eating more lutein in the diet seems to reduce the risk of CVD. However, taking oral lutein supplements does not seem to prevent CVD events or mortality. Details: One observational study has found that increased intake of dietary lutein is marginally associated with a reduced risk of developing coronary heart disease (14108). A meta-analysis including this and other studies shows that high dietary lutein intake or high lutein serum concentrations are associated with a 12% reduction in the incidence of coronary heart disease, an 18% reduction in stroke, and a 25% reduction in the incidence of metabolic syndrome when compared with low lutein intake or serum concentrations (97227). However, clinical research shows that taking lutein 10 mg plus zeaxanthin 2 mg daily for an average of 4.8 years does not decrease the risk of CVD-related mortality or cardiovascular events such as stroke, myocardial infarction, or angina when compared with no supplementation in patients 50-85 years old (94701). Unlike the analysis above, individual cardiovascular outcomes were not separately evaluated in this study. The effect of lutein on CVD in younger patients or in doses greater than 10 mg is unknown.
• Central serous retinopathy. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a supplement containing lutein 15 mg, vitamin C 288 mg, vitamin E 150 IU, zinc 9 mg, and copper 1.2 mg (Sante Lutax 15, Santen Pharmaceutical Co. Ltd) three times daily after meals for 6 months has no effect on mean best-corrected visual acuity, serous retinal detachment, or subfoveal fluid remission when compared with placebo in patients with central serous retinopathy (97224).
• Cervical cancer. It is unclear if oral lutein is beneficial for cervical cancer prevention. Details: Epidemiological research has found that low dietary intake of lutein is not associated with an increased risk for developing cervical cancer (60297).
• Child development. It is unclear if oral lutein is beneficial for child development. Details: Epidemiological research has found that a higher dietary intake of lutein in the first and second trimesters of pregnancy is associated with increased verbal intelligence and improved behavior in the child at 6-10 years of age. However, the ability to discriminate between a novel or familiar visual stimulus was reduced at about 6 months of age, and there were no effects on most cognitive outcomes in children aged 3-6 years (107106). Other epidemiological research has found that a higher dietary intake of lutein plus zeaxanthin in children aged 3-6 years may be associated with modestly improved executive function at 6-10 years. However, there were no effects on most cognitive outcomes in children aged 3-6 years or 6-10 years (109761).
• Choroideremia. It is unclear if oral lutein is beneficial for improving vision. Details: Preliminary clinical research shows that taking lutein 20 mg daily for 6 months does not improve vision in patients with choroideremia (60124).
• Cognitive function. It is unclear if oral lutein is beneficial for improving cognitive function. Details: A meta-analysis of clinical research shows that increased dietary lutein does not improve cognitive function measures, such as attention, executive function, or memory, when compared with placebo or an isocaloric meal (107082). However, the dietary source of lutein used in the included studies was heterogeneous and any conclusions remain unclear. Doses of lutein ranged from 8-12 mg daily, alone or in combination with daily zeaxanthin 2-26 mg and/or meso-zeaxanthin 10 mg and docosahexaenoic acid (DHA) 800 mg (107082). However, some preliminary clinical research in younger adults shows that taking lutein 10 mg and zeaxanthin 2 mg for one year modestly improves some measures of cognitive function, such as spatial memory, when compared with placebo (106348). Also, observational research has found that intake of choline and lutein plus zeaxanthin is positively associated with cognitive flexibility task performance speed. However, this association is not present with the intake of lutein plus zeaxanthin in the absence of choline (106354). Reasons for these discrepancies are not clear but may relate to lutein dose, treatment duration, or the addition of other nutrients to the diet or supplements.
• Colorectal cancer. It is unclear if oral lutein is beneficial for colorectal cancer prevention. Details: Some epidemiological research has found that higher dietary intake of lutein is associated with a reduced risk of developing colon cancer (3962). However, most epidemiological research has found that higher dietary intake of lutein is not associated with a reduced risk of colorectal cancer (34481,106372). It is not known if supplemental lutein has any effect on colorectal cancer risk.
• Depression. It is unclear if oral lutein is beneficial for depression. Details: A cross-sectional study in 8655 adults with cardiometabolic disease including diabetes, hypertension, coronary heart disease, heart failure, and stroke suggests that higher dietary lutein and zeaxanthin intake is associated with a 31% reduced risk of depression when compared with lower dietary intake. The study also found that adults with depression had lower dietary lutein and zeaxanthin intake than those without depression. Additionally, the study found a nonlinear U-shaped relationship between total dietary carotenoid intake and the risk of depression among patients with cardiometabolic disease, where the risk of depression decreased with increasing total dietary carotenoid intake up until an inflection point where the risk of depression increased with increasing total dietary carotenoid intake (112098). Further research is needed to establish causality.
• Diabetes. Observational research suggests that oral lutein may not be beneficial for the prevention of diabetes or diabetic complications. Details: Some epidemiological research has found that low serum levels of carotenoids, including lutein, are associated with impaired glucose tolerance. This may indicate that taking carotenoids such as lutein might reduce the risk of diabetes development (60161). However, population research has found that increasing intake of dietary lutein plus zeaxanthin does not decrease the risk of developing type 2 diabetes (14004,97227). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of lutein is not associated with reduced cardiovascular mortality over 14 years (109768).
• Diabetic retinopathy. It is unclear if oral lutein is beneficial in diabetic retinopathy. Details: Preliminary clinical research shows that taking lutein 10 mg daily for 36 weeks has no effect on visual acuity or glare sensitivity in patients with non-proliferative diabetic retinopathy (97223). Observational research in a small group of patients with non-proliferative diabetic retinopathy has also found that taking lutein 4 mg with zeaxanthin 0.5 mg daily for 4 months does not improve visual acuity, contrast sensitivity, or glare sensitivity when compared with zeaxanthin alone (100986).
• Esophageal cancer. It is unclear if oral lutein is beneficial for esophageal cancer prevention. Details: Population research has found that people who consume higher amounts of lutein and zeaxanthin in their diet have a 29% lower risk of developing esophageal squamous cell cancer when compared with those with lower intake (91159). It is unknown if supplemental lutein has any effect on esophageal cancer risk.
• Exercise-induced muscle soreness. It is unclear if oral lutein is beneficial in relieving muscle soreness due to exercise. Details: Some clinical research shows that taking a specific lutein-containing combination product (BioAstin, Cyanotech Corp.) containing haematococcus algae extract with astaxanthin 4 mg and lutein 480 mg daily for 3 weeks prior to exercise does not significantly reduce post-exercise muscle soreness when compared with placebo (19199). The effect of lutein alone is unclear.
• Fractures. It is unclear if oral lutein is beneficial for fracture prevention. Details: A meta-analysis of observational research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of hip fractures (97228).
• Gastric cancer. It is unclear if oral lutein is beneficial for gastric cancer prevention. Details: A meta-analysis of observational research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of developing gastric cancer (97231).
• Glaucoma. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with open-angle glaucoma shows that taking oral lutein 10 mg, zeaxanthin 2 mg, and meso-zeaxanthin 10 mg daily for 18 months increases macular pigment density, but does not affect visual function, when compared with placebo (109756).
• Hyperlipidemia. It is unclear if oral lutein is beneficial for hyperlipidemia. Details: A meta-analysis of clinical research shows that supplementation with lutein does not reduce the levels of total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol when compared with placebo (109757). Most publications included in this analysis evaluated lutein alone in healthy adults or in patients with age-related macular degeneration, two studies combined lutein with another ingredient, and one study evaluated zeaxanthin alone. The effect of lutein in patients with existing hyperlipidemia is unclear.
• Infertility. It is unclear if oral lutein is beneficial for infertility. Details: An observational study suggests that there is no association between dietary lutein intake and in-vitro fertilization (IVF) outcomes including good oocyte quality, embryo transfer success rates, clinical pregnancy rates, and successful term pregnancy rates in subfertile couples who are candidates for IVF (112097).
• Lung cancer. Research is conflicting whether oral lutein is beneficial for lung cancer prevention. Details: Epidemiological research has found that low serum levels of carotenoids, including lutein, are associated with an increased risk of lung cancer (12874). However, other epidemiological research has found that higher serum levels or higher dietary intake of lutein are not associated with a reduced risk of developing or dying from lung cancer (39690,60090,60160). Another large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests that dietary intake of lutein and zeaxanthin is protective against lung cancer as shown by a non-linear dose response curve, where lower doses of lutein and zeaxanthin are associated with a sharp decrease in the incidence of lung cancer, followed by a more gradual decrease in incidence at higher doses (112096).
• Macular telangiectasia type 2. It is unclear if oral lutein is beneficial for macular telangiectasia type 2. Details: In patients with macular telangiectasia type 2, observational research has found that taking a specific combination of lutein 10 mg, meso-zeaxanthin 10 mg, and zeaxanthin 2 mg (MacuShield; Alliance Pharmaceuticals) for at least 6 months, with an average duration of 15.7 months, was associated with a stabilization of visual acuity. Also, the number and size of cavitations in the macula were reduced (106355).
• Metabolic syndrome. Oral lutein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of observational research shows that high dietary lutein intake or high lutein serum concentrations are associated with a 25% reduction in the incidence of metabolic syndrome when compared with low lutein intake or serum concentrations (97227). Additional population research in females shows that the highest dietary intake of lutein plus zeaxanthin is associated with 54% reduced odds of developing metabolic syndrome when compared with the lowest intake. However, when supplements containing lutein plus zeaxanthin were included in the total intake, there was no association with metabolic syndrome (109760).
• Myopia. It is unclear if oral lutein is beneficial for myopia. Details: A very small clinical study in adults aged 20-50 years with high myopia shows that taking lutein 20 mg daily for 6 months does not improve macular pigment optical density, visual acuity, contrast sensitivity, or electroretinogram measurements when compared with placebo (112099). The validity of these findings is limited by the very small sample size and short study duration.
• Non-Hodgkin lymphoma. It is unclear if oral lutein is beneficial for Non-Hodgkin lymphoma prevention. Details: A meta-analysis of observational population research has found that increased intake of lutein/zeaxanthin in the diet is associated with an 18% lower risk of developing non-Hodgkin lymphoma when compared with low dietary intake. However, no dose-response relationship was reported (97229). It is unknown if supplemental lutein has any effect on non-Hodgkin lymphoma risk.
• Obesity. It is unclear if oral lutein is beneficial for obesity. Details: A small clinical trial in obese middle-aged individuals shows that taking lutein 20 mg daily in addition to following a low-calorie diet for 10 weeks does not affect most anthropometric or cardiometabolic indices when compared with a low-calorie diet alone. However, there was a small beneficial effect on body fat and total cholesterol levels (107107).
• Pancreatic cancer. It is unclear if oral lutein is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research has found that increased dietary intake of lutein and/or zeaxanthin is not associated with a reduced risk of pancreatic cancer (97230). The effects of supplemental lutein are unclear.
• Parkinson disease. It is unclear if oral lutein is beneficial for Parkinson disease prevention. Details: Population research has found that higher dietary intake of lutein is not associated with the risk of developing Parkinson disease (91164). The effects of supplemental lutein are unclear.
• Pre-eclampsia. It is unclear if oral lutein is beneficial for pre-eclampsia prevention. Details: Some epidemiological research has found that high plasma concentrations of lutein are associated with a decreased risk of pre-eclampsia (60142). Other epidemiological research has found that the highest dietary intake of lutein plus zeaxanthin during pregnancy is associated with 68% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). The effects of lutein supplements are unclear.
• Respiratory tract infections. It is unclear if oral lutein is beneficial in respiratory tract infection prevention or treatment. Details: Epidemiological research has found that high serum levels of lutein are not associated with a decreased incidence or severity of respiratory tract infections in the elderly (60152). The effects of supplemental lutein are unclear.
• Ulcerative colitis. It is unclear if oral lutein is beneficial for ulcerative colitis. Details: In patients in the remission phase of ulcerative colitis, observational research has found that a higher dietary intake of lutein plus zeaxanthin is associated with a reduced incidence of constipation, but not flatulence or feelings of urgency (tenesmus) (106362). The effects of supplemental lutein are unclear.
• Visual development. It is unclear if taking oral lutein during pregnancy can improve the visual acuity of the child. Details: Some observational research has found that higher maternal lutein levels are associated with a 22% to 40% lower risk of poor visual acuity in children at 3 years of age when compared with lower maternal lutein levels (102888). However, other epidemiological research has found that dietary intake of lutein plus zeaxanthin during the first or third trimesters of pregnancy is not associated with contrast vision or visual acuity in the child at 11-12 years of age (109759). The effects of lutein supplements are unclear. More evidence is needed to rate lutein for these uses.

(Read more about LUTEIN)

POSSIBLY EFFECTIVE

• Prostate cancer. Early findings suggests that oral lycopene might have a small benefit in preventing the development or recurrence of prostate cancer. Details: While some observational studies have found a reduced risk for prostate cancer from increased dietary lycopene intake (2405,2406,7772,7773,7895,12878,60304,60448,109432), others have found no significant association (34635,60334,60449,60457,60547). The most recent meta-analysis of these and other observational studies has found an overall modest benefit, suggesting that the risk of developing prostate cancer decreases by 1% for each additional 2 mg of daily dietary lycopene intake, and decreases by 3.5% for each 10 mcg/dL increase in plasma lycopene levels (98824). A subgroup analysis of some population research also suggests that the benefits from increased dietary lycopene may be limited to non-Hispanic White subjects (109432). Furthermore, a small clinical study in patients at high risk for developing prostate cancer with high-grade prostate intraepithelial neoplasia shows that taking lycopene (Lyc-O-Mato, LycoRed Natural Product Industries) 4 mg twice daily for one year might delay progression to prostate cancer when compared with no supplementation (14126). Numerous small heterogeneous studies have examined the effect of lycopene on serum prostate specific antigen (PSA) levels. One meta-analysis of 6 controlled clinical trials in patients with non-metastatic prostate cancer or prostatic intraepithelial neoplasia shows that taking lycopene 15-45 mg daily for 4 months does not reduce PSA levels when compared with control. However, in patients with a higher baseline PSA of over 6.5 mg/L, lycopene supplementation seems to reduce PSA levels when compared with control (105573). Other small, uncontrolled studies in patients in remission or with recurrent or metastatic prostate cancer suggest that taking lycopene (LycoRed, Jagsonpal Pharmaceuticals; Lyc-O-Mato, LycoRed Natural Product Industries Ltd.) 10-30 mg daily, or tomato products providing a mean of 43 mg lycopene daily, for 3-6 months reduces PSA levels when compared to baseline (60353,60397,60403,60417). Lycopene might also be beneficial in patients receiving surgical interventions. Small clinical studies in patients receiving orchiectomy for metastatic prostate cancer or radical prostatectomy show that taking lycopene 4 mg daily for 6 months or 30 mg daily for 3 weeks seems to reduce and normalize PSA levels when compared with baseline or control (7771,60328,60342). However, not all research has been positive. Two small clinical studies in patients with relapsed or androgen-independent prostate cancer show that taking lycopene 15-120 mg daily for up to one year does not affect PSA levels when compared with baseline (60372,60384). Many of these findings are limited due to a lack of a placebo control.

POSSIBLY INEFFECTIVE

• Bladder cancer. Dietary lycopene does not seem to affect the risk of bladder cancer. Details: Epidemiological research and population studies have not established a link between dietary intake of lycopene or lycopene serum levels and the risk of bladder cancer (2407,60411,60496,60533).
• Diabetes. Increased dietary lycopene intake does not seem to reduce the risk of diabetes or diabetic complications. Details: Population research has found that increasing intake of dietary lycopene does not decrease the risk of developing type 2 diabetes (14004,14361). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of lycopene is not associated with reduced cardiovascular mortality over 14 years (109768).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral lycopene is beneficial in patients with AMD; the available evidence is conflicting. Details: Some observational research has found that lycopene serum levels in the lowest quintile are associated with an almost two-fold increased risk for AMD when compared with levels in the highest quintile (6110). However, other population research has found no association between lycopene serum levels or dietary lycopene intake and the risk of developing AMD (5922,10902,14007,60585).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if dietary lycopene helps to prevent ALS. Details: Population research has found that the highest quintile of total dietary carotenoid intake is associated with a 25% lower risk of ALS when compared with the lowest quintile. However, no association was found for lycopene intake alone (90412).
• Asthma. It is unclear if oral lycopene reduces asthma exacerbations or prevents asthma. Details: Some preliminary clinical research in adults with stable asthma shows that taking a specific tomato extract product (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) providing lycopene 15 mg three times daily orally for up to 14 weeks does not reduce asthma exacerbations when compared with placebo (60482). However, other observational research has found that a higher dietary intake of lycopene is associated with at least a 20% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of lycopene supplements are unclear.
• Atherosclerosis. It is unclear if oral lycopene is beneficial in patients with atherosclerosis. Details: Some observational research has found that higher serum lycopene levels are associated with a lesser degree of aortic or carotid atherosclerosis (1446,60329,60463). Some observational research has also found that higher serum lycopene levels are associated with a lower risk of coronary heart disease and myocardial infarction in people with atherosclerosis (7897,60538). However, there does not seem to be a link between serum lycopene levels and the risk of ischemic stroke (1449).
• Benign prostatic hyperplasia (BPH). Small studies suggest that lycopene products might improve BPH symptoms. Details: While epidemiological evidence has not found an association between dietary lycopene and the development of BPH (60365), clinical research suggests that lycopene might improve BPH-related symptoms. One small clinical study in patients with BPH shows that taking lycopene (LycoVit powder, BASF) 15 mg daily for 6 months slows the progression of BPH and improves symptom scores when compared to baseline (60399). This finding is limited by the lack a statistical comparison to the control group. Research also suggests that combination products containing lycopene might improve BPH symptoms. These products have combined lycopene 2.1 mg with pumpkin seed oil 160 mg, small-flowered willow herb 500 mg, pygeum 15 grams, and saw palmetto 660 mg (ProstateEZE Max, Caruso's Natural Health) once daily for 3 months (92164); and lycopene 5 mg with saw palmetto 320 mg and selenium 50 mcg (Profluss, KonPharma) daily for 1 year (90354).
• Brain tumor. It is unclear if oral lycopene is beneficial for various types of brain tumor. Details: A small clinical study in patients with glioblastoma multiforme or anaplastic astrocytoma shows that taking lycopene 8 mg orally daily for 3 months does not improve the response to radiotherapy and paclitaxel when compared with placebo (60441).
• Breast cancer. It is unclear if oral lycopene reduces the risk of breast cancer. Details: Some observational research has found that higher levels of lycopene in the blood and breast adipose tissue are associated with reduced breast cancer risk (10132,34634,60549,60555). However, other epidemiological research has found that neither dietary lycopene intake nor lycopene serum levels are associated with breast cancer risk (10823,15751,60344,60468,60541). Also, some population research has found that there is a possible relationship between low serum lycopene levels and an increased risk of breast cancer in Black females, but not White females (60325).
• Cardiovascular disease (CVD). It is unclear if oral lycopene reduces the risk of CVD. Details: Most epidemiological research has found that higher serum levels of lycopene and increased dietary lycopene intake are associated with modestly reduced risk of adverse cardiovascular events, including reduced incidence of coronary heart disease, myocardial infarction, stroke, and mortality (7897,9594,10418,15749,60538,102178,109434). However, evidence from clinical trials shows that lycopene may not improve most risk factors for CVD. Meta-analyses of clinical research in healthy adults or patients with at least one cardiovascular risk factor show that taking lycopene 1.44 to 75 mg daily does not improve blood pressure, lipid levels, or endothelial function when compared with control (95777,105575). These findings are limited by the heterogeneity of the included trials.
• Cataracts. It is unclear if oral lycopene is beneficial for reducing the risk of cataracts. Details: One epidemiological study has found that serum lycopene levels are inversely associated with the risk of developing cataracts (60203). However, other population studies have found no association between lycopene serum levels or dietary intake of lycopene and the development of cataracts (3219,3220,60299).
• Cervical cancer. It is unclear if oral lycopene reduces the risk of cervical cancer. Details: Epidemiological research has found that higher serum lycopene levels or higher dietary lycopene intake is associated with a reduced risk of cervical intraepithelial neoplasia and invasive cervical cancer (60429,60430,60439,60566). However, other studies have not shown this association (60388,60517,60521).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with prostatitis and chronic pelvic pain syndrome shows that taking a specific combination of lycopene 5 mg with selenium 50 mcg and saw palmetto 320 mg (Profluss, KonPharma) daily for 8 weeks reduces pain scores by 52%, compared with a 26% reduction with saw palmetto alone (60442). It is unclear if this effect is due to lycopene, the other ingredients, or the combination.
• Cognitive function. It is unclear if oral lycopene is beneficial for improving cognitive function and memory. Details: Observational research in healthy adults has found that consuming more lycopene in the diet over 22 years is associated with lower odds of poor cognitive function (104468).
• Colorectal cancer. It is unclear if lycopene reduces the risk for colorectal cancer; the available research is conflicting. Details: Some population research has found that the highest tertile of dietary lycopene intake is associated with a 50% reduced risk for colorectal cancer when compared with the lowest tertile (2407,38845). However, other epidemiological research has found no association between dietary lycopene intake and the risk of colorectal cancer, regardless of smoking status, drinking status, geographical location, gender, and tumor location (3962,34542,95778).
• Esophageal cancer. It is unclear if oral lycopene is beneficial for preventing esophageal cancer. Details: A meta-analysis of population research has found that high dietary intake of lycopene is associated with a 25% reduced odds of developing esophageal squamous cell carcinoma when compared with low dietary intake of lycopene (91159).
• Exercise-induced asthma. It is unclear if oral lycopene is beneficial for preventing exacerbations of exercise-induced asthma. Details: One very small clinical trial in children and adults with exercise-induced asthma shows that taking a specific tomato extract product (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) providing lycopene 30 mg daily for 1 week seems to reduce the incidence of exercise-induced asthma exacerbations, but does not improve certain measures of lung function, when compared to baseline (7898). However, another very small study in adolescent athletes with exercise-induced asthma shows that taking the same product and dose for 1 week does not improve post-exercise lung function or reduce exacerbations when compared with placebo (60358). This study may have been underpowered to detect a difference between groups.
• Exercise-induced muscle damage. Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adult long-distance runners shows that taking a combination product (Lycored Ltd.) containing lycopene 5 mg, other carotenoids 4 mg, folic acid 0.1 mg, tocopherols 4 mg, and rosemary extract orally once daily for 4 weeks reduces muscle damage associated with a 2-hour run when compared with placebo (98825).
• Gastric cancer. It is unclear if oral lycopene reduces the risk of gastric cancer. Details: Preliminary observational research in adult males has found that high dietary intake of lycopene is associated with 0.87 lower odds of having stomach cancer when compared with low dietary intake (109436).
• Gingivitis. Small studies suggest that ingesting or injecting oral lycopene products might improve gingivitis. Details: Preliminary clinical research shows that taking a specific oral lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 8 mg daily for 2 weeks, or receiving a single injection of lycopene gel 2 mg into the gums, reduces gingivitis when compared with placebo (60400,60473). However, using a combination product (Lycotas, Intas Pharmaceuticals) containing lycopene 2 mg, vitamin C 50 mg, vitamin A 2500 units, zinc sulfate 20.6 mg, and chromium picolinate 75 mcg orally twice daily for 2 weeks does not improve moderate gingivitis or mild to moderate periodontitis when compared with placebo in people who have also undergone scaling and root planning (92172).
• Helicobacter pylori. It is unclear if oral lycopene helps to eradicate H. pylori. Details: A small clinical study in patients diagnosed with H. pylori shows that adding lycopene 30 mg daily for 1 month to standard therapy with metronidazole, amoxicillin, omeprazole, and bismuth does not increase the rate of H. pylori elimination when compared with standard therapy alone (60480).
• Human papillomavirus (HPV). It is unclear if oral lycopene is beneficial in patients with HPV. Details: Epidemiological research in females has found that higher plasma levels of lycopene are associated with a faster rate of oncogenic HPV clearance, with an average of 8.5 months, when compared with lower levels of plasma lycopene, with an average of 11-12 months (12177).
• Hyperlipidemia. Most research shows that oral lycopene doesn't reduce low-density lipoprotein (LDL) cholesterol levels; however, effects on other lipid levels are unclear. Details: A subgroup meta-analysis of 3 small clinical studies in adults with hyperlipidemia shows that taking lycopene 7-15 mg daily or tomato juice containing lycopene 2.5 mg 4 times weekly for 8 weeks does not improve LDL cholesterol levels when compared with control (105575). Another subgroup meta-analysis of 9 studies in adults without hyperlipidemia shows that consuming lycopene, in supplements or in tomato products, also does not seem to reduce LDL cholesterol levels when compared with both active and inactive controls (105575). This finding is limited by the heterogeneity of interventions and patient populations. In contrast, one small clinical study in Japanese patients with borderline high cholesterol shows that taking 50 grams of a semi-dried tomato containing lycopene 22-27.8 mg daily for 12 weeks modestly reduces LDL cholesterol levels, but does not affect high-density lipoprotein (HDL) cholesterol levels, when compared with taking 50 grams of tomato without lycopene (102180). Subgroup meta-analyses also show that taking lycopene does not reduce triglyceride levels or improve HDL cholesterol levels (105575). However, a meta-analysis of 14 small clinical trials including healthy subjects and subjects with metabolic disorders shows that taking lycopene 6-75 mg orally daily for 1 week to 6 months moderately improves both HDL cholesterol and triglyceride levels when compared with control. A subgroup analysis suggests lycopene may improve lipid levels in unhealthy, but not healthy, subjects. However, the validity of this study is limited by high heterogeneity and the exclusion of LDL cholesterol levels from the analysis (109431). Also, a clinical study in patents with ischemic heart failure shows that taking lycopene 25 mg daily for 8 weeks modestly reduces levels of triglycerides (109773). In postmenopausal females, taking a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 4 mg orally twice daily for 6 months also modestly increases triglyceride levels (109694). However, there was no effect on other lipid levels in either of these studies (109694,109773).
• Hypertension. Small clinical studies suggest that some lycopene products might reduce blood pressure in patients with hypertension. However, lycopene does not seem to reduce the risk for hypertension. Details: Observational research has found no link between serum lycopene levels and the risk for hypertension (60419). Additionally, lycopene supplements do not seem to reduce blood pressure in patients without hypertension or with pre-hypertension (42079,105572,105575). However, some clinical research suggests that lycopene may be beneficial for lowering blood pressure in people with hypertension. A network meta-analysis of 4 small clinical trials in patients with hypertension shows that taking standardized tomato extract containing lycopene 10-30 mg daily for 4-12 weeks reduces systolic and diastolic blood pressure by about 8 mmHg and 4 mmHg, respectively, when compared with placebo. This benefit was not seen with supplements containing only lycopene or tomato products without standardized lycopene content (105572). Specific tomato extract products (Lyc-O-Mato or Tomato Nutrient Complex, LycoRed, Ltd.), were used in some studies (60415,102182).
• Lung cancer. It is unclear if oral lycopene is beneficial in patients with lung cancer. Details: Some epidemiological research has found that higher dietary lycopene intake or serum levels are linked to a decreased risk of lung cancer (2595,60332,60363,60550). However, other epidemiological research has found no association between dietary intake or blood levels of lycopene and lung cancer risk (60316,60520,60522,60554).
• Male infertility. It is unclear if oral lycopene is beneficial in male patients with infertility. Details: A small clinical study in males with idiopathic infertility shows that taking lycopene 2 mg orally twice daily for 3 months improves sperm concentration, motility, and morphology when compared with baseline (60340). The validity of this finding is limited by the lack of a control group.
• Melasma. Topical lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with melasma shows that applying a sunscreen cream containing lycopene 0.05% and wheat bran extract 3.45% twice daily for 12 weeks seems to modestly reduce the severity of melasma, but not the area of affected skin, when compared with a placebo cream (105569).
• Menopausal symptoms. Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with menopausal symptoms shows that taking a specific oral combination of lycopene with calcium, vitamin D3, astaxanthin, and citrus bioflavonoids (Cor.Con. International) daily for 8 weeks reduces hot flashes, incontinence, joint pain, anxiety, and depression when compared with no treatment (19198). It is not clear if this effect is due to lycopene, other ingredients, or the combination.
• Obesity. It is unclear if a diet high in lycopene helps to reduce weight. Details: A small clinical study in obese adults shows that ingesting a drink with a carrot paste containing lycopene 7.6-8.6 mg, along with either high-lutein kale paste or low-lutein cabbage paste, daily for 8 weeks does not reduce body weight or waist circumference, but seems to modestly reduce the amount of visceral fat, when compared with baseline (105574). This finding is limited due to a lack of comparison to the control group, which consumed a carrot paste containing no lycopene.
• Oral leukoplakia. It is unclear if oral lycopene is beneficial in patients with oral leukoplakia. Details: A small clinical study in patients with oral leukoplakia shows that taking a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 2-4 mg orally twice daily for 3 months improves clinical and histological symptoms in a dose-dependent manner when compared with placebo (15748). Preliminary clinical research also shows that taking lycopene 6 mg, along with vitamin E 400 IU and selenium 200 mcg twice daily, for 3 months has a large beneficial effect on lesion size when compared with placebo (109772).
• Oral submucous fibrosis. Small studies suggest that oral lycopene might slightly improve mouth opening in patients with oral submucous fibrosis. It is unclear if lycopene reduces pain or burning sensation. Details: A meta-analysis of 5 small clinical studies in patients with oral submucous fibrosis, usually from chewing betel nuts and/or tobacco, shows that taking lycopene 4-8 mg twice daily for 1-3 months seems to improve maximal mouth opening, but not pain, when compared with control (105570). Clinical studies reported an average mouth opening increase of 3.5-4 mm when compared to baseline (60381,98823,102181). It is unclear if this improvement is clinically significant. Furthermore, although two clinical studies using specific tomato extracts (LycoRed, Jagsonpal Pharmaceuticals; MintovitL by Obsurge Biotech Limited) show that lycopene also reduces the burning sensation in the mouth (98823,102181), the meta-analysis did not confirm this benefit (105570). All of the available studies have been conducted in India and Saudi Arabia; it is unclear if these results are generalizable to other locations.
• Osteoporosis. It is unclear if oral lycopene reduces the risk of osteoporosis. Details: Population research in adults at least 50 years of age has found that high dietary intake of lycopene is not associated with bone mineral density or osteoporosis risk when compared with low dietary intake (107289).
• Ovarian cancer. It is unclear if oral lycopene reduces the risk of ovarian cancer. Details: Some epidemiological evidence has found that a diet rich in carotenoids, including lycopene, is associated with a decreased risk of premenopausal ovarian cancer (10133). However, other epidemiological research has found no association (60373,60534).
• Overall mortality. It is unclear if oral lycopene reduces the risk of overall mortality. Details: Preliminary observational research in adults undergoing cancer screening has found that moderate dietary intake of lycopene, defined as 5.61-8.43 mg daily, is associated with a lower risk of overall mortality and cardiovascular disease-related mortality when compared with low dietary intake of lycopene, defined as less than 2.79 mg daily. However, higher dietary intake of lycopene of 8.44 mg or greater was not associated with mortality risk (109434).
• Pancreatic cancer. It is unclear if oral lycopene helps to prevent pancreatic cancer. Details: Epidemiological research has found that high dietary intake of lycopene is associated with a reduced risk of pancreatic cancer. Intake in the highest quartile was associated with a 31% reduction in risk when compared with the lowest quartile (15750).
• Parkinson disease. It is unclear if oral lycopene helps to prevent Parkinson disease. Details: Epidemiological research has found that neither dietary intake nor blood levels of lycopene is associated with the risk of developing Parkinson disease (91164).
• Polymorphous light eruption (PMLE). Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with PMLE shows that taking a combination of lycopene 2.5 mg, beta-carotene 4.7 mg, and Lactobacillus johnsonii 500 million CFU (Inneov Sun Sensitivity, Laboratoires Innéov) daily for 12 weeks reduces skin lesion severity after a single exposure to light when compared with placebo (90276). It is not clear if this effect is due to lycopene, other ingredients, or the combination.
• Pre-eclampsia. It is unclear if oral lycopene is beneficial in patients with pre-eclampsia. Details: Epidemiological research has found that the highest intake of lycopene during pregnancy is associated with 45% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). However, results from clinical research are mixed. One clinical study in healthy primigravidae shows that taking a specific oral lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 2 mg twice daily, starting between weeks' 16 and 20 of pregnancy and continuing until delivery, lowers mean diastolic blood pressure and reduces the incidence of pre-eclampsia, intra-uterine growth retardation, and preterm labor when compared with placebo (60337). However, another clinical study in this same population shows that taking this same lycopene supplement only once daily, starting between weeks' 12 and 20 of pregnancy, does not reduce the incidence of pre-eclampsia when compared with placebo. Furthermore, the rates of preterm labor and low birth weight were higher in those taking lycopene when compared with placebo (60428). The reasons for these conflicting findings are unclear; larger, high-quality studies are needed to clarify these findings.
• Renal cell carcinoma. It is unclear if oral lycopene reduces the risk for renal cell carcinoma. Details: Observational research has found no association between dietary lycopene intake and the risk of developing renal cell carcinoma (60379).
• Sunburn. Small studies suggest that consuming tomato paste with oral lycopene might prevent sunburn. Details: Small clinical studies in healthy volunteers shows that taking lycopene 10-16 mg daily for 12 weeks, in the form of tomato paste or a tomato extract (Lyc-O-Mato), may provide some protection against experimentally-induced sunburn when compared to baseline or control (23012,60324,60452). More evidence is needed to rate lycopene for these uses.

(Read more about LYCOPENE)

EFFECTIVE

• Bowel preparation. Various magnesium salts are used for cleansing the bowel prior to procedures such as colonoscopy. Details: Various magnesium salts, including citrate, hydroxide, oxide, and sulfate, are ingredients in bowel preparation products available over-the-counter or by prescription only.
• Constipation. Magnesium salts are effective when used orally to treat constipation short-term. It is unclear if magnesium is beneficial for chronic idiopathic constipation (CIC). Details: Magnesium citrate, sulfate, and hydroxide salts are commonly used as laxatives. Magnesium citrate 8.75-25 grams has been used; magnesium hydroxide 2.4-4.8 grams, as 30-60 mL of milk of magnesia, has also been used (15). Magnesium sulfate, which seems to have the most potent effect, has been used as 10-30 grams (15,6430). Magnesium salts should only be used for occasional treatment of constipation, and doses should be taken with a full 8-ounce glass of water. There is also interest in using magnesium for symptomatic relief of CIC. A small clinical study in patients with CIC who are not taking chronic medications shows that taking magnesium oxide 1.5 grams in three divided doses daily for 28 days increases spontaneous bowel movements when compared with placebo (104397). It is unknown if magnesium is beneficial for CIC when used long-term.
• Dyspepsia. Magnesium salts are effective when used orally as antacids. Details: Magnesium carbonate, hydroxide, oxide, or trisilicate salts are used orally as antacids to reduce symptoms of gastric hyperacidity or gastroesophageal reflux. Magnesium hydroxide has the fastest onset of action. The onset for magnesium carbonate is slower due to its crystal structure. Magnesium trisilicate has the slowest onset and longest duration of action due to poor solubility (6844). Doses used include magnesium hydroxide 400-1200 mg (5-15 mL of milk of magnesia) up to four times daily, or magnesium oxide 800 mg daily (15).
• Eclampsia. Magnesium sulfate is considered the drug of choice for control of seizures. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (15,12591,12592,61012,61184). Typical doses include 4-6 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). Meta-analyses of clinical research show that treatment with IV or IM magnesium reduces the risk of seizure recurrence by 33% to 69% when compared with phenytoin, and by 47% to 60% when compared with diazepam (19960,60818,60954,60964,61105). One preliminary clinical study shows that lower doses of IV magnesium sulfate (9 grams loading dose and maintenance of 2.5 grams every 4 hours for 24 hours) are as effective as higher doses (14 grams loading dose and maintenance of 5 grams every 4 hours for 24 hours) for reducing the recurrence of eclamptic seizures (89383). It is generally recommended that treatment be continued for at least 24 hours after the last seizure (15). Oral magnesium has not been evaluated for eclampsia.
• Hypomagnesemia. Hypomagnesemia can be effectively treated with oral or parenteral magnesium. Details: Taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesemia associated with alcoholism, cirrhosis of the liver, congestive heart failure (CHF), severe or prolonged diarrhea or vomiting, kidney dysfunction, inflammatory bowel disease (IBD), pancreatitis, malabsorption syndromes, and other conditions (6280,6281,8088,8089). The dose and salt of magnesium for oral replacement therapy should be chosen carefully to avoid causing diarrhea. The gluconate and chloride salts cause less diarrhea, while the oxide salt is more likely to cause diarrhea and should be avoided. Magnesium chloride should also be avoided due to poor solubility which decreases absorption (6430,8099,10664). Orally, magnesium sulfate 3 grams every 6 hours for four doses has been used for hypomagnesemia (15). Parenteral magnesium doses must be individualized according to serum magnesium levels, but a typical starting dose for mild deficiency is 1 gram of magnesium sulfate intramuscularly (IM) every 6 hours for 4 doses (15). For more severe deficiency, 5 grams of magnesium sulfate may be given as an intravenous (IV) infusion in 1 liter of dextrose 5% or normal saline solution over 3 hours (15).
• Pre-eclampsia. Magnesium sulfate is considered the drug of choice for seizure prophylaxis in patients with pre-eclampsia. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during pre-eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (12591,12592,61012,61184). Some meta-analyses show that IV administration of magnesium sulfate reduces the risk of eclampsia when compared with placebo, phenytoin, or diazepam in patients with pre-eclampsia (19960,60818,60960,60979). A typical initial dose is 4-5 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams of magnesium sulfate per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). The optimal duration of prophylaxis has not been determined. A meta-analysis suggests that using a shorter duration of 12 hours or less is not associated with an increase in risk of eclamptic seizures when compared with regimens of 24 hours or longer (108732). However, studies are likely underpowered due to the low incidence of eclampsia. Oral magnesium has been evaluated for the prevention of pre-eclampsia in healthy adults, but taking magnesium citrate 300 mg daily, starting at 12-20 weeks' gestation and continuing until delivery, does not reduce the incidence of pre-eclampsia when compared with placebo (103724).

LIKELY EFFECTIVE

• Cerebral palsy. Most evidence shows that antenatal magnesium reduces the risk of cerebral palsy in preterm infants, although there are some inconsistent results. Details: Most clinical studies and meta-analyses show that antenatal magnesium sulfate reduces the risk of cerebral palsy by about 32% and the risk of motor dysfunction by about 45% in preterm infants (60882,60915,60927,60931,61001,97485,103734,103754). The lowest effective dose of magnesium sulfate seems to be 4 grams intravenously, with or without a maintenance dose of 1 gram/hour until birth or for 24 hours. In obese females, a higher dose, based on body weight, may be needed (97485,97495,103734,103754). However, some studies have inconsistent results (8093,19998,98293,98295,112784). Giving females at risk of imminent preterm birth (prior to 32 weeks), intravenous magnesium sulfate 4.5 grams over 20 minutes followed by 1 gram per hour until birth or for 24 hours, in addition to a standard treatment protocol, does not reduce the incidence of cerebral palsy (112784). Oral magnesium has not been evaluated for this purpose.
• Seizures. Intravenous magnesium sulfate is used for treating seizures of various etiologies. Details: Intravenous magnesium sulfate may be useful for controlling seizures associated with epilepsy, glomerulonephritis, hypothyroidism, and acute nephritis in children (15). Oral magnesium has not been evaluated for this purpose.
• Torsades de pointes. Intravenous magnesium sulfate is the first-line treatment for torsades de pointes after measures to correct precipitating factors have been unsuccessful. Details: Intravenous magnesium sulfate has been used successfully to treat the life-threatening ventricular tachycardia, torsades de pointes (15,6844). The Advanced Cardiac Life Support (ACLS) guidelines of the American Heart Association recommend a dose of 1 to 2 grams diluted in 50-100 mL Dextrose 5% solution given IV over 5-60 minutes, followed by a continuous IV infusion of 0.5-1 gram/hour.

POSSIBLY EFFECTIVE

• Arrhythmia. Magnesium sulfate is effective for the specific type of ventricular tachycardia known as torsades de pointes, and seems to be helpful for treating other types of arrhythmias. Evidence for the role of oral or intravenous magnesium in preventing postoperative arrhythmias is conflicting. Details: Administering magnesium intravenously or orally may be helpful for treating atrial and ventricular tachycardia and fibrillation, and supraventricular tachycardia (9497,13352,13354,13355,13356,60804,60829,60877,61113,111696). Arrhythmias associated with congestive heart failure have been treated with magnesium sulfate 8 grams infused over 12 hours (9497). For rate control in atrial fibrillation, magnesium sulfate 2.5 grams IV over 20 minutes, followed by 2.5 grams IV over 2 hours has been used (13356). For paroxysmal supraventricular tachycardia, single doses of 1-4 grams of magnesium chloride have been used (13352). For atrial tachycardia, 2 grams of magnesium sulfate in 10 mL of dextrose 5% solution has been given IV over 1-10 minutes, followed by 5-10 grams of magnesium sulfate in 250-500 mL dextrose 5% solution as an IV infusion over 5 hours (13354,13355). Research on the effects of intravenous magnesium for preventing arrhythmias after cardiac surgery is conflicting. Some meta-analyses show that intravenous magnesium reduces the risk of atrial fibrillation, ventricular arrhythmias, or supraventricular arrhythmias following cardiac surgery by 23% to 48% when compared with placebo (60814,60826,60828,60838,61008,61033,61181,97487,97490). Doses of magnesium sulfate used include 30 mg/kg in 500 mL normal saline (97490), or 80-100 mg/kg added to the cardioplegia solution (97487). Also, one small study in adults after CABG surgery suggests that taking magnesium hydroxide 1600 mg orally reduces arrhythmia as effectively as receiving magnesium sulfate 2000 mg intravenously (99315). However, other meta-analyses that only include higher-quality trials show that magnesium supplementation does not reduce the risk of ventricular or supraventricular arrhythmias following cardiac surgery (61010,61024,61031,105081). A meta-analysis of clinical trials of intravenous magnesium for prevention of new-onset atrial fibrillation after non-cardiac surgeries shows that it does not reduce the incidence significantly when compared with placebo (112778). However, there was a high risk of bias in the analysis, and variability in types of surgery, and the salt and dose of magnesium used.
• Asthma. Parenteral magnesium sulfate can help to reverse severe acute asthma attacks and reduce the need for hospital admission. Oral or nebulized magnesium, however, does not seem to be beneficial. Details: Overall, a single dose of intravenous magnesium seems to improve pulmonary function in acute asthma exacerbation and reduce the risk of hospitalization, particularly in patients with severe asthma, and those who have failed initial treatment with nebulized albuterol and intravenous corticosteroids (60888,90023,96483,104398,107365). The typical dose used for adults is 2 grams of magnesium sulfate infused over 20 minutes (15). For children, 25-75 mg/kg, to a maximum of 2 grams, infused over 20-30 minutes has been used (15,96483,107365). However, a post-hoc analysis of one large clinical trial (104400) designed to assess nebulized magnesium in children with acute asthma has found that adding IV magnesium to nebulized magnesium is associated with greater odds of hospitalization when compared with no IV magnesium (105919). This post-hoc analysis did not differentiate between precautionary and necessary hospitalizations. Although some clinical research in patients with acute asthma exacerbation shows that nebulized magnesium in combination with albuterol significantly improves airway function when compared with albuterol alone, the benefit is not likely to be clinically relevant (90016). Most evidence, including larger clinical trials, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920). Oral magnesium also does not seem to be beneficial. A meta-analysis of small clinical trials in children and adults with asthma shows that taking magnesium supplements orally does not improve lung function or reduce bronchodilator use when compared with control (104404).
• Colorectal cancer. Increasing dietary magnesium intake seems to lower the risk of colon cancer but not rectal cancer. Details: Epidemiological research shows that increased dietary magnesium intake is associated with a reduced risk of colon cancer, but the risk of rectal cancer is not affected (89387,90017,90027,101355).
• Diabetes. Low dietary magnesium may increase the risk of developing type 2 diabetes, but evidence on the use of supplements for treating type 2 diabetes is conflicting. Details: Higher dietary magnesium intake is associated with lower fasting insulin concentrations and a reduced risk of developing type 2 diabetes in adults and obese children (13369,15548,96473,97486,98294,103736,105918,106920). In people with existing type 2 diabetes, hypomagnesemia is found in 25% to 38% of patients, especially in those with poorly controlled diabetes (1172). Population research in adults with type 2 diabetes also shows that a dietary magnesium intake of less than 250 mg daily is associated with a 56% higher risk of mortality. Preliminary subgroup analyses suggest that the risk of mortality is higher in those with glycated hemoglobin (HbA1C) levels above 7% (110051). A meta-analysis of small, heterogeneous clinical studies in adults with type 2 diabetes suggests that magnesium may modestly reduce HbA1C in patients with hypomagnesemia, but not in patients with normal magnesium levels, when compared with control (105075). Individual clinical studies using magnesium supplements in patients with type 2 diabetes or insulin resistance have shown mixed results. Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity, as well as reduce the risk of developing diabetes in high-risk patients (10664,12582,13376,60854,99313,106920), but other research shows no effect (1171,1172,13379,13380,112780). Discrepancies in these findings might reflect differences in magnesium salts and doses used, or differences in baseline magnesium status in study subjects.
• Hypercholesterolemia. Magnesium may help improve lipid levels by a small amount in people with this condition. Details: There is some evidence that taking magnesium oxide 1 gram orally daily for 6 weeks can produce small decreases in low-density lipoprotein (LDL) and total cholesterol levels, and small increases in high-density lipoprotein (HDL) levels in patients with hypercholesterolemia. However, magnesium does not seem to improve lipoprotein (a) levels (1193). Magnesium may also lower triglycerides in people with hypertriglyceridemia (97494).
• Metabolic syndrome. Low dietary and serum levels of magnesium seem to be associated with the development of metabolic syndrome. Details: Higher magnesium intake from diet and supplements is associated with a 27% lower risk of developing metabolic syndrome in healthy females (13371) and a 31% lower risk in healthy young adults (14304). Additional epidemiological research suggests that people with low serum magnesium levels are 6-7 times more likely to have metabolic syndrome than people with normal magnesium levels (13372). In a population analysis of over 6000 individuals without metabolic syndrome at baseline, the risk of developing this condition over a 6-year follow-up period was reduced by 16% in the highest quintile of dietary magnesium intake (median intake 371 mg daily) when compared with the lowest quintile (median intake 203 mg daily). Some, but not all, research suggests that the hazard ratio for metabolic syndrome in relation to magnesium intake may be U-shaped, with higher risk at intakes below about 150 mg daily and above 600 mg daily (108963). A combination of magnesium 20 mEq daily and potassium 40 mEq daily (magnesium potassium citrate) taken orally for 16 weeks reverses metabolic side effects of chlorthalidone, such as increased fasting plasma glucose and hypokalemia, more effectively than potassium chloride 40 mEq daily alone (112932).
• Osteoporosis. Increased dietary and supplemental magnesium intake seems to increase bone mineral density and decrease bone loss in postmenopausal patients. Details: Preliminary clinical research shows that taking magnesium hydroxide orally, 300-1800 mg daily for 6 months, then 600 mg daily for 18 months, or magnesium citrate orally 1830 mg daily for 30 days, might reduce bone loss and bone turnover in postmenopausal patients with osteoporosis (9104,60928). Some epidemiological research also suggests that magnesium intake is related to increased bone mineral density (12501,12502,12503,12504,90014), although not all studies have found an association (12505,98286).
• Postoperative pain. Injectable magnesium has been used with promising results for reducing pain postoperatively. Details: Intravenous magnesium sulfate, 5-50 mg/kg bolus followed by a continuous infusion of 6 mg/kg or 500 mg hourly during surgery, seems to reduce the 24-hour postoperative use of intravenous morphine by 24% when compared with placebo (19968). Adding intravenous magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Meta-analyses also support that adjunctive intravenous and intrathecal administration of magnesium improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728); however, it appears to be less effective than dexmedetomidine (105082). A moderate-sized clinical study in patients undergoing total knee arthroplasty in China shows that adding magnesium sulfate 2.5 mg/mL to the periarticular infiltration analgesia (PIA) cocktail reduces pain scores, limits the use of postoperative morphine, prolongs analgesia, and reduces markers of inflammation when compared with the usual PIA cocktail (111181). Administering magnesium intravenously also seems to be helpful for pain control after hysterectomy. A 3-gram IV bolus of magnesium sulfate followed by an infusion of 0.5 grams per hour for 20 hours has been used. Lower doses were not effective (6848). In males undergoing laparoscopic radical resection for gastrointestinal cancer, administering intravenous magnesium intraoperatively, as a loading dose of 40 mg/kg followed by 15 mg/kg/hour through the end of surgery, reduces postoperative catheter-related bladder discomfort and analgesic requirements, when compared with placebo (112783). However, intravenous magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium intravenous infusion does not reduce pain when compared with saline in children after tonsillectomy or after elective strabismus surgery (98282,105077).
• Premenstrual syndrome (PMS). Taking magnesium orally seems to relieve symptoms of PMS. Details: There is some evidence that magnesium supplementation can improve symptoms, including mood changes and fluid retention, in some patients with PMS (1187,1188,6847). Doses used include magnesium oxide 333 mg daily for 2 menstrual cycles, or magnesium pyrrolidone carboxylic acid equivalent to 360 mg elemental magnesium three times daily, from the 15th day of the menstrual cycle until onset of menstrual flow (1187,1188). Taking magnesium orally in a dose of 360 mg (elemental magnesium) three times daily for 2 months seems to prevent premenstrual migraine (1186,6847). A combination of magnesium 200 mg daily plus vitamin B6 50 mg daily seems to reduce anxiety-related premenstrual symptoms, including nervous tension, mood swings, irritability, and anxiety, when compared with placebo (8555).
• Vasospastic angina. Intravenous magnesium seems to prevent coronary spasm in patients with this condition. Details: Clinical research shows that administration of intravenous magnesium sulfate 65 mg/kg infused over 20 minutes dilates coronary arteries and suppresses acetylcholine-induced coronary spasms when compared with infusion of a dextrose solution in patients with vasospastic angina (8091).

POSSIBLY INEFFECTIVE

• Altitude sickness. Taking magnesium citrate orally does not seem to reduce acute altitude sickness risk. Details: Clinical research shows that taking magnesium citrate 1200 mg daily orally in three divided doses, beginning 3 days prior to mountain ascent and continuing until mountain descent, does not reduce the risk of acute altitude sickness when compared with placebo (60801).
• Athletic performance. Taking magnesium orally does not seem to improve energy or endurance during athletic activity. Details: Most evidence suggests that taking magnesium orally doesn't increase energy and endurance during athletic activity. Magnesium oxide, aspartate, and orotate salts don't seem to improve exercise performance when used alone or in combination with potassium (2825,2826,2828,2829,2830,60751).
• Bronchiolitis. Intravenous or nebulized magnesium is not beneficial in infants with this condition. Details: Clinical research shows that administering a single IV dose of magnesium sulfate 100 mg/kg to infants with acute bronchiolitis does not improve, and may actually worsen, symptoms when compared with placebo (97482). A clinical study in infants with moderate to severe bronchiolitis shows that adding nebulized magnesium sulfate 40 mg/kg to nebulized epinephrine does not reduce hospital stay or the need for ventilator or oxygen support when compared with epinephrine alone (99317). Oral magnesium has not been evaluated for this use.
• Chemotherapy-induced peripheral neuropathy. Research on the effects of intravenous infusions of magnesium and calcium for preventing oxaliplatin neurotoxicity are inconsistent, but higher quality studies seem to show no benefit. Details: Pooled analyses of cohort studies and clinical trials show that calcium and magnesium infusions can decrease the incidence of severe oxaliplatin-induced neurotoxicity (90028,90029,90031). However, when only clinical trials are considered, the infusions do not appear to be helpful (90005,90029,90031,96474,96479).
• Complex regional pain syndrome. Intravenous magnesium is not beneficial in complex regional pain syndrome type 1. Details: Clinical research shows that receiving magnesium sulfate 70 mg/kg intravenously at the rate of 25 mL/hour for 4 hours each day for 5 days does not improve pain or level of impairment when compared with placebo in patients with chronic complex regional pain syndrome type 1 (89395).
• Emergence delirium. The majority of small clinical studies in adults and children undergoing various surgeries suggest that intravenous (IV) magnesium doesn't reduce the risk of emergence delirium. Details: A small clinical study in adults undergoing surgery for endovascular aortic aneurysm repair shows that administering IV magnesium 30 mg/kg as a loading dose, followed by a 10 mg/kg/hour infusion for the duration of surgery, does not improve agitation or delirium scores when compared with administering saline (111182). Similarly, a small clinical study in children ages 2-5 years undergoing elective strabismus surgery shows that administering IV magnesium during anesthesia does not seem to prevent the occurrence of emergence delirium when compared with administering saline (105077). In a meta-analysis of 8 clinical trials in children aged 2-16 years undergoing general anesthesia for oral or ophthalmic surgery, giving IV magnesium as a 30 mg/kg loading dose followed by a 10 mg/kg/hour infusion, or as a single dose of 15-30 mg/kg, does not reduce emergence delirium scores, and may actually prolong emergence times (108729). However, there is some conflicting evidence. In patients undergoing radical mastectomy, giving intraoperative magnesium sulfate 30mg/kg over 1 hour, followed by 10 mg/kg/hour until the end of surgery, reduces emergence agitation (odds ratio 0.26) when compared with placebo (112781).
• Menopausal symptoms. Oral magnesium oxide does not seem to be beneficial for menopausal hot flashes. Details: A small, low quality study in postmenopausal patients with a history of breast cancer shows that taking magnesium oxide 400-800 mg orally daily reduces hot flashes when compared with baseline (102454). However, a larger, higher quality clinical study using magnesium oxide 800-1200 mg daily did not show any benefit when compared with placebo (98290).
• Muscle cramps. Oral magnesium does not seem to improve muscle cramp frequency or intensity. Details: Meta-analyses of small clinical trials show that magnesium supplementation for 3-6 weeks does not decrease the frequency or intensity of skeletal muscle cramps, whether the cramps are idiopathic or due to liver cirrhosis or pregnancy, when compared with placebo (90022,104395).
• Sickle cell disease. Intravenous magnesium does not add any benefit to standard therapy for sickle cell disease in children. Details: Clinical research shows that giving magnesium sulfate 40-100 mg/kg (maximum of 2 grams per dose) intravenously every hour for 6-8 doses as an adjunct to standard therapy does not decrease hospital stay, pain, or opioid use, or improve quality of life, when compared with standard therapy and placebo in children with sickle cell disease (89399,98283,101356). Oral magnesium has not been evaluated for this purpose.
• Stillbirth. Magnesium administered during pregnancy does not reduce stillbirth risk. Details: A meta-analysis of clinical research shows that magnesium supplementation does not significantly decrease the risk of stillbirths when administered during pregnancy (60925,60978).
• Tetanus. Intravenous magnesium sulfate does not seem to improve outcomes in patients with this condition. Details: A meta-analysis of clinical research shows that intravenous magnesium sulfate does not reduce mortality when compared with placebo or diazepam in patients with tetanus (61020). While some research shows that magnesium reduces the duration of hospitalization and the need for ventilation when compared with diazepam (61170), magnesium does not seem to improve these outcomes when compared with placebo (60860).
• Traumatic brain injury (TBI). Magnesium does not improve clinical outcomes in patients with moderate to severe TBI. Its effect in patients with concussions is unclear. Details: A meta-analysis of four clinical trials shows that treatment with magnesium does not significantly improve neurological outcomes or reduce the risk of mortality when compared with placebo in patients with moderate to severe TBI (60905). A small observational cohort study in adolescents with concussions has found that adding oral magnesium 400 mg twice daily for 5 days to standard treatment with acetaminophen and ondansetron is associated with a trend toward reduced symptom severity when compared with standard treatment alone (104401). The validity of this study is limited by its observational nature and small cohort size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Intravenous magnesium does not seem to help reduce symptoms of alcohol withdrawal but may reduce the duration of alcoholic delirium. Details: Preliminary clinical research shows that administration of four intramuscular injections of magnesium sulfate 2 grams at 6-hour intervals does not reduce symptoms of alcohol withdrawal when compared with saline (61063). A small observational study in patients with alcoholic delirium has found that administering magnesium sulfate IV 50 mg/kg every 8 hours, in addition to usual sedation, is associated with a reduction of delirium by approximately 2 days, or 4 days when given every 12 hours in addition to dexmedetomidine, when compared with usual sedation alone (111180). However, half of patients had hypomagnesemia at baseline; it is unclear if effects would be similar for patients with normal magnesium levels. Oral magnesium has not been evaluated for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral magnesium for allergic rhinitis, there is insufficient reliable information about the clinical effects of magnesium for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral magnesium is beneficial in children with ADHD. Details: Children with ADHD seem to have lower magnesium levels in their blood and hair (9969,100262,100263). A small clinical study in children aged 7-12 years with ADHD and magnesium deficiency shows that taking magnesium aspartate and lactate 6 mg/kg daily for 6 months might improve hyperactivity and magnesium levels when compared with control (1189). Another small clinical study in children with ADHD but without magnesium deficiency shows that taking magnesium 6 mg/kg daily along with vitamin D 50,000 IU weekly for 8 weeks may modestly improve emotional problems, but not inattention or hyperactivity, as measured on the strength and difficulties questionnaire (SDQ), when compared with placebo (105914).
• Back pain. It is unclear if oral or intravenous magnesium is beneficial for acute or chronic back pain in adults. Details: One open-label clinical study in adults with acute low-back pain shows that taking magnesium 365 mg once daily in addition to taking etodolac 400 mg twice daily for 10 days does not further reduce pain when compared with taking etodolac alone (105913). Magnesium has also been tried for chronic back pain. A small clinical study in patients with chronic low-back pain shows that receiving magnesium sulfate 1 gram in 250 mL normal saline intravenously every 4 hours for 2 weeks, followed by magnesium gluconate 100 mg and magnesium oxide 400 mg by mouth daily for 4 weeks, reduces pain severity when compared with placebo (90035). It is unclear if oral magnesium used alone is beneficial.
• Bariatric surgery complications. It is unclear if oral magnesium supplementation improves metabolic parameters after bariatric surgery. Details: A retrospective study of over 3000 post-bariatric surgery patients suggests that those who take oral magnesium supplements providing 100-450 mg elemental magnesium daily may have improved metabolic parameters over 4 years of follow-up. When patients taking magnesium supplements were compared with those not taking supplements, 11% and 18% had type 2 diabetes, respectively, 30% and 42% had hypertension, respectively, and 16% and 23% had elevated low-density lipoprotein (LDL) cholesterol levels, respectively. For patients with hypomagnesemia at baseline, supplementation seemed to result in greater benefits (108968).
• Bipolar disorder. Taking magnesium orally might improve manic symptoms in some people with bipolar disorder; however, it is unclear how it compares to current standard of care. Details: One preliminary clinical study shows that magnesium 40 mEq daily (Magnesiocard) for 32 weeks has similar effects to lithium in up to 50% of patients treated for rapid cycling bipolar affective disorder (61022). Another preliminary clinical study shows that magnesium oxide 375 mg orally daily plus verapamil 80 mg taken four times daily reduces manic symptoms more effectively than verapamil alone in patients with mania (60742).
• Cancer-related neuropathic pain. It is unclear if intravenous magnesium is beneficial for this condition. Details: Single 500 mg to 1 gram doses of magnesium sulfate seem to relieve neuropathic pain for up to four hours when compared to baseline (6846). The validity of this finding is limited by the lack of a comparator group.
• Chemotherapy-induced leukopenia. It is unclear if oral magnesium is beneficial in pediatric patients at risk for cisplatin-induced febrile neutropenia. Details: A small clinical study in children with solid tumors aged 9 years and older shows that taking magnesium 250 mg daily while receiving cisplatin-based chemotherapy reduces febrile neutropenia by 47% and septic shock by 57% when compared with not receiving magnesium. Results from this study suggest that four pediatric patients need to take oral magnesium to avoid one case of febrile neutropenia (104394).
• Cardiac arrest. Intravenous magnesium does not seem to be helpful in cardiac arrest; however, the risk of sudden cardiac death seems to be inversely correlated to higher plasma magnesium levels or dietary intake. It is unclear if magnesium supplementation is associated with similar risk reduction. Details: Administering magnesium intravenously doesn't seem to improve successful resuscitation in people with cardiac arrest (1190). However, higher plasma magnesium levels and higher dietary magnesium intake might reduce the risk of sudden cardiac death, possibly by protecting against fatal ventricular arrhythmias. In the Nurses' Health Study, the risk of sudden cardiac death was 77% lower in females with the highest quartile of plasma magnesium levels when compared with the lowest quartile. Also, the risk was 37% lower in females with the highest quartile of dietary magnesium intake when compared with the lowest quartile (17132).
• Cardiovascular disease (CVD). Evidence regarding the effect of dietary magnesium on CVD risk is conflicting. Details: Epidemiological research in some populations shows that increased dietary magnesium intake is associated with decreased mortality due to strokes, coronary heart disease, ischemic heart disease, and heart failure, but other epidemiological research does not show any effect on these risks (89391,90003,90009,90030,90036,103735). Reasons for the discrepancies may be related to serum levels of magnesium at baseline, risk of cardiovascular disease at baseline, use of concomitant medications such as diuretics, or the presence of concomitant conditions such as kidney dysfunction. A population analysis conducted in Denmark has found that magnesium intake from drinking water may be associated with cardiovascular mortality. The overall risk of cardiovascular death and death due to stroke was reduced by 4% in the lowest 3 quintiles of intake when compared with the highest quintile. However, the risk of death due to acute myocardial infarction was increased by 22% in the lowest quintile when compared with the highest (108726). The relevance of these results is unclear, given that the main dietary source of magnesium is food rather than drinking water.
• Chronic fatigue syndrome (CFS). Limited evidence suggests that magnesium may help improve CFS symptoms, but this is controversial. Details: In people with low red blood cell magnesium, there is some evidence that intramuscular injections of 1 gram magnesium sulfate given once weekly for 6 weeks might improve CFS symptoms (7556). However, there is additional evidence that most patients with CFS have normal magnesium stores, and measurement of red cell magnesium is a poor indicator of total magnesium stores (7557,8084,8085,8086,8087).
• Chronic obstructive pulmonary disease (COPD). Intravenous, but not nebulized, magnesium may be helpful in acute exacerbations of COPD. Details: Administering magnesium sulfate intravenously, 1.2-2.5 grams over 20 minutes, might be helpful for treating acute exacerbations of COPD (1208,6844,103733). Also, giving magnesium sulfate 2 grams intravenously seems to improve exercise capacity when compared with placebo (89384). A meta-analysis of studies using intravenous magnesium sulfate for COPD exacerbations shows that it reduces hospital admission and mean length of stay and improves dyspnea scores when compared with placebo. Based on the relative risk identified in the included studies, seven patients would need to receive intravenous magnesium to prevent one hospitalization. However, intravenous magnesium sulfate does not change the need for non-invasive ventilation and the available research did not evaluate intensive care unit (ICU) admission (108967). Nebulized magnesium has also been evaluated. In patients experiencing a COPD exacerbation, clinical research shows that administering nebulized magnesium sulfate with albuterol three times at 30-minute intervals does not improve pulmonary function as measured by the forced expiratory volume in 1 second (FEV1) when compared with placebo (89393). Also, a meta-analysis of a small number of low-quality studies shows that nebulized magnesium does not reduce hospital admission or the need for ventilatory support, although it might modestly improve dyspnea scores and reduce ICU admissions, when compared with placebo (108967).
• Cluster headache. It is unclear if a single intravenous dose of magnesium sulfate is beneficial for cluster headaches. Details: Administering magnesium sulfate intravenously, 1 gram over 5 minutes, seems to improve cluster headaches when compared with baseline(1184). The validity of this finding is limited by the lack of a comparator group.
• Cognitive impairment. It is unclear if oral magnesium is beneficial for cognitive impairment. Details: A large observational study in adults with end-stage renal disease on hemodialysis suggests that serum magnesium levels of 20.2-22.3 mg/dL are associated with the lowest odds of mild cognitive impairment, while serum magnesium levels below and above that range of values are associated with increased odds of mild cognitive impairment (111695).
• Coronary heart disease (CHD). It is unclear if magnesium supplementation is beneficial for CHD. Details: Clinical research shows that magnesium oxide 800-1200 mg daily for 3 months reduces platelet-dependent thrombosis by 35% when compared with placebo in patients with CHD (60759). It is unclear if this effect improves clinical outcomes. The effect of magnesium supplementation on coronary artery calcium has also been studied. A meta-analysis of 3 clinical studies in 196 patients with chronic kidney disease (CKD) shows that taking magnesium or increasing the concentration of magnesium in dialysate does not improve coronary artery calcification (CAC) scores when compared with standard therapy. However, magnesium reduced carotid intima-media thickness (111179). Similarly, a large clinical study in patients with CKD shows that taking slow-release magnesium hydroxide (Mablet, Denmark) 360 mg twice daily for 12 months does not slow the progression of CAC scores when compared with placebo (111178). This study may not have been adequately powered to detect a difference between groups.
• Depression. It is unclear if magnesium is beneficial for the treatment or prevention of depression in adults. Details: Some population research shows that dietary intake of elemental magnesium between 76-360 mg daily is associated with a reduced risk of depression, but there was no association with greater amounts of magnesium, and other population research shows no association at any intake level (96480,98289). For treatment of mild to moderate depression, one preliminary clinical study shows that taking magnesium chloride 2 grams orally daily for 6 weeks reduces depression scores by 56% and anxiety scores by about 52% when compared to baseline (96477). The validity of these findings is limited by the lack of a comparator group. However, a small clinical study in adults with recurrent depression shows that taking magnesium aspartate 120 mg daily for 8 weeks, along with fluoxetine, does not improve depression scores when compared with patients taking fluoxetine and placebo (111185). Similarly, a very small crossover clinical study in adults with mild or moderate treatment-resistant depression shows that administering a single dose of IV magnesium sulfate 4 grams does not improve depression scores when compared with an infusion of 5% dextrose (96481). However, scores were evaluated 24 hours post-infusion which may be too soon to detect improvement. Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that elemental magnesium in doses of 100-400 mg is not recommended for adjunctive or monotherapy use in patients with depression (110318).
• Diabetic foot ulcers. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with grade 3 diabetic foot ulcers shows that taking magnesium oxide 250 mg plus vitamin E 400 IU daily for 12 weeks modestly reduces ulcer size when compared with placebo (101436). It is unclear if this effect is due to magnesium, vitamin E, or the combination.
• Exercise-induced muscle soreness. It is unclear if oral magnesium reduces muscle soreness in adults after resistance training. Details: A very small study in healthy adults, ages 19-23, shows that taking magnesium glycinate 350 mg daily for 10 days seems to reduce muscle soreness after bench press exercise when compared with placebo (104399).
• Fibromyalgia. It is unclear if oral magnesium is beneficial for this condition. Details: A small clinical study shows that taking magnesium chloride orally 100 mg once daily for one month reduces mild to moderate, but not severe, stress associated with fibromyalgia when compared with placebo. It also reduces pain levels, but not to a clinically significant extent, and it does not affect sleep, fatigue, or quality of life (108964). Another small clinical study shows that taking magnesium citrate 300 mg daily for 8 weeks improves some symptoms of fibromyalgia, such as number of tender points and depression, when compared to baseline (89385). The validity of this finding is limited by the lack of a comparator group. A small clinical study shows that taking a combination of magnesium hydroxide and malic acid (Super Malic tablets) orally decreases fibromyalgia-related pain and tenderness in some patients when compared with placebo (3262). It is unclear if this effect is due to magnesium, malic acid, or the combination.
• Fractures. Population research suggests that higher intakes of magnesium may reduce fracture risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is associated with a 34% lower odds of fracture when compared with lower magnesium intake (101395).
• Gastric cancer. Population research suggests that higher intakes of magnesium may reduce gastric cancer risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is not associated with a reduced risk for gastric cancer when compared with lower intake (103730).
• Hearing loss. Oral magnesium may prevent and improve hearing loss due to environmental factors or loud noises. Details: Clinical research in healthy military recruits shows that taking magnesium aspartate 167 mg daily for 2 months prevents hearing loss from exposure to loud noises during basic military training when compared with placebo (1205). Also, in patients with acute-onset hearing loss that was not caused by environmental factors, taking magnesium aspartate 167 mg daily for 8 weeks seems to improve hearing loss when compared with placebo (60813).
• Hypertension. Oral magnesium supplementation may modestly reduce blood pressure, although these changes are not likely to be considered clinically significant. Details: Most research shows that taking oral magnesium supplements in daily doses that are at least as high as the Recommended Dietary Allowance (RDA) for adults and up to 1000 mg daily can lower diastolic blood pressure by about 2 mmHg in adults with or without hypertension (1192,1199,9465,15165,18111,96482). Significantly lower doses do not seem to have this effect (1180,1195,1197,8098). The effect of magnesium on systolic blood pressure is conflicting. One meta-analysis shows that taking magnesium 240-970 mg daily does not lower systolic blood pressure (15165). However, more recent meta-analyses show that taking magnesium 120-970 mg daily can lower systolic blood pressure in a dose-dependent manner by about 2-4 mmHg in patients with or without hypertension (18111,96482). In 2022, the US Food and Drug Administration (FDA) approved a qualified health claim stating that inconsistent and inconclusive evidence suggests that diets with adequate magnesium may reduce the risk of high blood pressure. Products bearing this claim must provide at least 84 mg of magnesium daily, but no more than 350 mg daily (107451).
• Hypokalemia. It is unclear if intravenous or oral magnesium is beneficial for hypokalemia in patients with normal magnesium levels. Details: A preliminary retrospective observational study in patients with hypokalemia and unknown serum magnesium levels has found that administering oral or intravenous magnesium is not associated with improved time to normalization of serum potassium levels when compared with no magnesium treatment (110049). However, hypokalemia with concurrent hypomagnesemia can impede potassium repletion and exacerbate hypokalemia-induced rhythm disturbances. Standard of care in patients with hypokalemia and known hypomagnesemia includes prompt treatment with magnesium (110063).
• Impaired glucose tolerance (prediabetes). It is unclear if oral magnesium is beneficial for prediabetes. Details: Preliminary clinical research in patients with prediabetes shows that taking magnesium oxide 250 mg orally daily for 12 weeks does not improve fasting blood glucose levels, insulin resistance, or glycated hemoglobin (HbA1C) levels when compared with placebo. Taking magnesium also did not affect blood pressure, body weight, triglyceride levels, or low-density lipoprotein cholesterol levels; however, it did modestly improve high-density lipoprotein cholesterol levels (110053).
• Insomnia. Oral magnesium may modestly improve sleep complaints in adults, but evidence is conflicting. Details: A meta-analysis of two small clinical studies in healthy older adults with or without insomnia suggests that taking magnesium reduces the time to fall asleep by an average of 17 minutes when compared with placebo (105917). However, it does not increase the time spent asleep. Also, these findings are limited by imprecision and a high risk of bias. Studies included in the analysis used elemental magnesium 500-729 mg daily (as magnesium oxide) for up to 8 weeks (102458,105917). Another small clinical study in patients with poor sleep quality and low magnesium status shows that taking elemental magnesium 320 mg (as magnesium citrate) in divided doses daily for 7 weeks does not improve sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), when compared with a sodium citrate placebo (102456). A very small crossover clinical study in patients aged 18-40 years without a sleep disorder shows that taking a combination of magnesium 300 mg, L-tryptophan 1000 mg, glycine 3000 mg, tart cherry 220 mg, and theanine 200 mg for 3 days reduces the time to fall asleep by about 24 minutes, increases total time asleep by about 22 minutes, and improves sleep efficiency, but does not improve the total time in bed or wakefulness after falling asleep when compared with cellulose placebo (111184). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous magnesium sulfate can reduce the risk for intraventricular hemorrhage in neonates. Details: A meta-analysis of clinical research in premature infants shows that if the mother received antenatal intravenous magnesium sulfate, the infant had a non-significant trend toward a reduced risk of intraventricular hemorrhage when compared with infants whose mothers received placebo (103727). This analysis may have been insufficiently powered to detect a difference between groups.
• Kidney stones (nephrolithiasis). Taking magnesium orally may prevent the recurrence of kidney stones, although evidence is conflicting. Details: Prophylactic treatment with magnesium hydroxide, 200 mg twice daily for one year, followed by 500 mg daily for another year, might decrease the recurrence rate of calcium stone formation (2007). However, magnesium oxide does not seem to benefit patients considered to be recurrent calcium stone formers when compared with placebo, no treatment, or chlorthalidone (8097,38501,61199). Magnesium oxide 300 mg in combination with vitamin B6 10 mg daily seems to decrease urinary oxalate levels in people with hyperoxaluria who have previously had kidney stones (1201), but it is unclear if this effect translates into a reduced incidence of kidney stones.
• Liver cancer. Increased dietary magnesium intake is linked with a lower risk of liver cancer. Details: Observational research in retired older Americans has found that higher dietary magnesium intake is associated with a 35% lower risk of liver cancer when compared with lower intake. This association was especially strong in persons who were moderate or heavy alcohol users (105080).
• Migraine headache. Oral magnesium may help prevent migraine in some adults and children. Also, intravenous magnesium may help treat migraine in adults, but evidence is conflicting. Details: Small clinical studies in adults with migraine suggest that taking oral high-dose magnesium citrate 600-1830 mg daily in divided doses for up to 3 months seems to modestly reduce the frequency and severity of headaches when compared with baseline or placebo (4891,9498,60902). Limited evidence suggests that adding oral magnesium to conventional treatment may also be beneficial. A clinical study in adults with migraine living in Iran shows that taking magnesium oxide 250 mg twice daily in addition to sodium valproate 200 mg twice daily for 12 weeks modestly reduces severity and duration of migraine, but not migraine frequency, when compared with taking sodium valproate alone (105915). It is unclear if these improvements would be considered clinically significant. In contrast, one small clinical study shows that taking magnesium does not reduce migraine frequency and severity by at least 50% in adults when compared with placebo (10661). For treatment of migraine, some adults with normal magnesium levels respond to intravenous (IV) magnesium sulfate 1 gram over 5 minutes, but most patients who benefit have low magnesium levels at baseline (1185,6844). Effects of IV magnesium in patients with unknown magnesium levels are conflicting. Some preliminary clinical research shows that magnesium 1-2 grams IV alleviates acute migraine for up to 2 hours, but other research has found no benefit (89388,97493,98285). In children, treatment with magnesium oxide orally 15 mg/kg daily in 3 divided doses for up to 16 weeks reduces the frequency and severity of migraine headaches when compared with placebo (10663). However, adding magnesium sulfate 400 mg orally daily to ibuprofen or acetaminophen does not further reduce migraine severity in children (89396).
• Myocardial infarction (MI). Research on the effects of intravenous or oral magnesium after myocardial infarction are conflicting. Details: Administering magnesium intravenously doesn't seem to reduce mortality after an acute MI (8999,13357,13358,13359,13360,19990,60872,61082), although there is some conflicting evidence from a meta-analysis of clinical research that shows that intravenous magnesium sulfate may reduce short-term mortality by 55% when compared with placebo (60795,60895). Clinical research with oral magnesium supplementation has found no benefit (1198,6844).
• Neonatal encephalopathy. Intravenous magnesium may improve short-term outcomes in neonates with encephalopathy. Details: A meta-analysis of clinical research shows that intravenous magnesium may improve short term outcomes of neonatal encephalopathy (hypoxic ischemic encephalopathy, HIE). However, long term outcomes are not affected (90025).
• Nocturnal leg cramps. It is unclear if oral magnesium is helpful for nocturnal leg cramps. Details: Some clinical research in adults with nocturnal leg cramps shows that taking magnesium oxide 865 mg daily at bedtime for 4 weeks does not reduce the frequency of leg cramping episodes when compared with placebo (96478). However, four weeks may be too short a time to see a benefit. In other clinical research, taking oral magnesium oxide monohydrate 226mg daily at bedtime for 60 days reduces the frequency of leg cramps when compared with placebo. This reduction was not seen after 30 days. Magnesium also reduced cramp duration and improved sleep quality, but did not affect pain scores, at 60 days when compared with placebo (106919).
• Nonalcoholic fatty liver disease (NAFLD). Oral magnesium hydroxide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with NAFLD shows that taking magnesium hydroxide 150 mg and L-carnitine 2000 mg daily for 16 weeks does not improve liver stiffness scores when compared with baseline or controls who took placebo for 8 weeks followed by this magnesium and L- carnitine combination for 8 weeks. Taking magnesium and L-carnitine also did not improve levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) when compared to baseline (111177).
• Obesity. Evidence on the use of magnesium for weight loss in obese patients is conflicting; any benefit is likely small at best. Details: A meta-analysis of 7 clinical studies in obese patients shows that taking magnesium reduces body mass index (BMI) by 0.3 when compared with control (103723). Another meta-analysis of 7 studies in obese patients shows that while magnesium supplementation does not reduce weight, it reduces waist circumference by 2 cm when compared with placebo (103729). Interestingly, subgroup analyses did not find that the dose of magnesium or baseline magnesium levels impacted effectiveness. One subgroup analysis found that magnesium supplementation lasting 12 weeks or less seemed to be more beneficial for obesity than supplementation lasting longer than 12 weeks (103723).
• Overall mortality. It is unclear if oral or IV magnesium reduces the risk of overall mortality. Details: A meta-analysis of heterogeneous observational studies has found that increased dietary magnesium intake, but not supplemental magnesium intake, is associated with a modestly reduced risk of overall mortality (105073). A meta-analysis of 3 small, low-quality clinical studies in ICU patients shows that administering IV magnesium 24-30 mmol or as a target-directed dose for 3 days reduces overall mortality when compared with patients who did not receive magnesium (111290). However, some studies included patients with hypomagnesemia; it is unclear if effects would be similar for patients with normal levels of magnesium.
• Osteoarthritis. Population research has not found a link between magnesium intake and osteoarthritis risk. Details: Observational research has found that dietary and supplemental magnesium intake is not associated with the risk of developing osteoarthritis (101395).
• Pain (acute). It is unclear if intravenous magnesium is helpful for acute pain associated with kidney dysfunction. Details: Preliminary clinical research in patients with renal colic shows that intravenous (IV) magnesium sulfate, 50 mg/kg infused over 20 minutes, is as effective as IV morphine sulfate 0.1 mg/kg for controlling acute renal pain at 20 minutes after the dose (107367).
• Pain (chronic). Population research suggests that higher intakes of magnesium may modestly reduce the risk for chronic pain. Details: A cross-sectional observational study has found that increased magnesium intake is associated with a 7% to 8% reduced risk for chronic pain. The association was found to be stronger in females than in males (103732).
• Perioperative anxiety. It is unclear if oral magnesium is beneficial for perioperative anxiety. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves anxiety and depression scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Postoperative sore throat. It is unclear if topical magnesium sulfate is beneficial for reducing sore throat pain after endotracheal intubation. Details: Preliminary clinical research in patients undergoing endotracheal intubation for surgery shows that using a gargle containing magnesium sulfate 20% with lidocaine, 20 minutes before anesthesia induction, is less effective for reducing sore throat pain than a gargle containing dexmedetomidine and lidocaine (112779). The study did not include a comparison to lidocaine alone.
• Physical performance. Oral magnesium may modestly improve physical performance in otherwise healthy, elderly females. Details: Clinical research in otherwise healthy elderly females shows that taking a magnesium oxide supplement (Easymag, Sanofi-Aventis) 900 mg daily for 12 weeks modestly improves walking speed and chair stand speed in elderly females when compared with no treatment (90026).
• Polycystic ovary syndrome (PCOS). It is unclear if oral magnesium is beneficial for improving metabolic indices in patients with PCOS. Details: Two small clinical studies in patients with PCOS show that taking magnesium oxide orally, 250 mg daily for 8 weeks, does not affect insulin resistance, beta-cell function, lipid levels, or insulin sensitivity when compared with placebo (103725,105887). Other clinical research in patients with PCOS shows that taking magnesium oxide orally, 250 mg daily for 10 weeks, improves subjective measures of quality of life, fatigue, and emotional functioning, but not objective measures such as alopecia, abnormal uterine bleeding, or acne, when compared with placebo (108965). A clinical study using a combination of magnesium 250 mg with vitamin E 400 mg daily for 12 weeks shows a modest reduction in insulin resistance, insulin levels, and triglyceride levels, but not other lipid levels, when compared with placebo (100264). It is unclear if these beneficial effects are due to magnesium, vitamin E, or the combination.
• Postoperative sleep disturbance. It is unclear if oral magnesium is beneficial for postoperative sleep disturbances. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves sleep scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Pregnancy-related leg cramps. It is unclear if oral magnesium reduces leg cramps during pregnancy; evidence is conflicting. Details: One small clinical study in patients with pregnancy-related leg cramps shows that taking magnesium bisglycinate chelate 300 mg daily for 4 weeks reduces the frequency and intensity of leg cramps when compared with placebo (99318). A smaller clinical study in this population shows that taking a specific mixture of magnesium lactate and citrate (Nycoplus Magnesium) providing elemental magnesium 120 mg in the morning and 240 mg in the evening for 3 weeks reduces the frequency of cramps when compared with placebo (1194). However, not all research agrees. One small clinical study using this same supplement and dose for 2 weeks found no benefit when compared with placebo (17463). It is possible that a 2-week duration of treatment is too short to be beneficial. Finally, a meta-analysis of these studies and one other more recent clinical study shows that taking magnesium does not reduce the frequency or improve the resolution of pregnancy-related leg cramps when compared with placebo (105916). This analysis may not have been adequately powered to detect a difference between treatment groups.
• Pre-procedural sedation. It is unclear if intravenous magnesium is beneficial when administered in addition to propofol for sedation. Details: A moderate-sized study of adults aged 65-79 years old undergoing endoscopic retrograde cholangiopancreatography (ERCP) shows that administering a single intravenous bolus of magnesium sulfate 40 mg/kg prior to the procedure reduces intraoperative propofol requirements by about 21% and reduces some peri-procedural adverse events including the incidence of respiratory depression and involuntary movement when compared with control. However, there were no differences in recovery time, hemodynamic parameters, or the incidence of hypotension, bradycardia, perioperative nausea or vomiting, lethargy, or arrythmias (111694).
• Preterm labor. The use of magnesium sulfate to inhibit uterine contractions in preterm labor (tocolysis) is controversial. However, its use for the purpose of fetal neuroprotection for up to 48 hours is supported by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine. Details: Magnesium is given intravenously during preterm labor in an effort to improve fetal neurological outcomes. The typical dosage of magnesium sulfate is 4 grams infused IV over 10-30 minutes, followed by a maintenance infusion of 1-4 grams/hour for 48 hours or until birth. Use beyond 5-7 days has been associated with hypocalcemia and bone abnormalities in the fetus (15,12590,12594). Some meta-analyses of clinical research suggest that magnesium sulfate is more effective at delaying delivery by 48 hours when compared with oxytocin receptor blockers, nitrates, beta-mimetics, and/or placebo (20263,61021). Administration of magnesium during preterm labor has been shown to reduce the risk of cerebral palsy and motor dysfunction in the infant (60882,60915,60927,60931,61001,97485,103734,103754).
• Pseudoxanthoma elasticum (PXE). It is unclear if oral magnesium is beneficial for PXE. Details: Preliminary clinical research in patients with PXE shows that taking magnesium oxide 800 mg (500 mg of elemental magnesium) twice daily for one year tends to reduce calcification of elastic skin fibers when compared with placebo, but the effect is not statistically significant (101393). This study was limited by small size and insufficient power to detect smaller effects.
• Restless legs syndrome (RLS). It is unclear if oral magnesium is beneficial for RLS. Details: Some observational research has found that hypomagnesemia is associated with RLS; however, not all research agrees (8096,9472). Preliminary clinical research in adults with RLS who are beginning treatment with pramipexole shows that also taking magnesium oxide 250 mg orally daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052). Other low-quality clinical research in adults with RLS or periodic limb movement during sleep shows that taking magnesium 12.4 mmol orally in the evening for 4-6 weeks decreases movement and increases sleep when compared with baseline (9466). The validity of this finding is limited by the lack of a comparator group.
• Sarcopenia. It is unclear if oral magnesium is beneficial for the prevention or treatment of sarcopenia. Details: Population research in older adults has found that lower dietary intake of magnesium is associated with sarcopenia. However, the effect of magnesium supplementation on sarcopenia prevention or treatment has not been evaluated (110055).
• Stroke. Increased dietary magnesium may decrease stroke risk, and using a magnesium-containing salt substitute may improve neurological performance post-stroke. However, intravenous magnesium has not demonstrated benefit. Details: Most population research has found that increased dietary intake of magnesium is associated with decreased stroke risk and decreased mortality from stroke (9001,9002,90013,90030,90036,92107,103736). In patients who have had a stroke, a preliminary clinical study shows that using a salt substitute providing the Dietary Reference Intake (DRI) of magnesium and potassium for 6 months improves neurological performance when compared with using regular salt (97491). However, intravenous (IV) magnesium does not seem to be beneficial in patients who have had a stroke. Large prospective clinical trials show that IV magnesium given within 12 hours of acute stroke does not reduce mortality or disability in most patients when compared with placebo. However, one subgroup analysis suggested that IV magnesium might benefit patients with lacunar (non-cortical) stroke (13361,90021). IV magnesium also doesn't seem to reduce cardiovascular complications after acute stroke. A secondary analysis of a clinical trial in patients after ischemic and hemorrhagic stroke shows that giving IV magnesium does not reduce serious cardiac adverse events when compared with placebo (104393). Another secondary analysis of this trial shows that giving IV magnesium prior to arrival at the hospital and within 2 hours of a hemorrhagic stroke does not reduce hematoma volume on hospital arrival, hematoma expansion during hospital admission, or functional outcomes at 3 months (108733).
• Subarachnoid hemorrhage. Intravenous magnesium sulfate may reduce the risk of adverse outcomes in people with subarachnoid hemorrhage, but evidence is conflicting. Details: There is mixed evidence regarding the effect of magnesium sulfate in managing aneurysmal subarachnoid hemorrhage. One meta-analysis of clinical research shows that intravenous magnesium sulfate 64-144 mmol/day for 10-18 days reduces the risk of poor outcomes following aneurysmal subarachnoid hemorrhage, including death, vegetative state, or dependency, by 46% when compared with control (60932). Also, meta-analyses of clinical research show that intravenous magnesium reduces the risk of delayed cerebral ischemia by 27% when compared with placebo (60944,89398). However, these results were not confirmed in other meta-analyses (60973,90034).
• Thrombocytopenia. It is unclear if intravenous magnesium sulfate is beneficial in patients with thrombotic thrombocytopenic purpura (TTP). Details: Addition of intravenous magnesium sulfate as a 6-gram loading dose followed by 6 grams infused over 24 hours for 3 days, to standard treatment for TTP does not reduce the time to normalization of the platelet count, the incidence of TTP-related organ dysfunction, or the recurrence rate, when compared with standard treatment alone (112777). This study may have been underpowered to detect a difference.
• Urinary incontinence. Although there has been interest in using oral magnesium for urinary incontinence, there is insufficient reliable information about the clinical effects of magnesium for this purpose. More evidence is needed to rate magnesium for these uses.

(Read more about MAGNESIUM)

EFFECTIVE

• Manganese deficiency. Oral and intravenous manganese can prevent and treat manganese deficiency. Details: Taking manganese orally or intravenously is effective for preventing or treating manganese deficiency (15). However, the incidence of manganese deficiency is not well documented. Long-term home parenteral nutrition should provide no more than 55 mcg daily of manganese for adults or 1 mcg/kg daily (up to 50 mcg) of manganese for children unless clinically indicated (96416,99302). A clinical trial in children aged 8-14 months who are manganese deficient shows that taking manganese in addition to other vitamins and minerals in a 30 mL beverage six days per week for up to 14 months promotes growth when compared with placebo (19348).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal manganese is beneficial in patients with allergic rhinitis. Details: A small clinical study in patients with chronic allergic rhinitis shows that using an isotonic seawater nasal spray enriched with manganese (Sterimar Mn, Laboratori Baldacci) four puffs daily for 5 months, in addition to standard treatment with oral antihistamines, nasal corticosteroids, and nasal decongestants, reduces the number of acute exacerbations by about three when compared with the standard treatment alone (99416). However, the effect of the manganese in this product is unclear since nasal lavage with a plain saline nasal spray also helps in allergic rhinitis.
• Chronic obstructive pulmonary disease (COPD). Intravenous manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated for exacerbation of COPD shows that intravenous supplementation with manganese 0.4 mg, selenium 100 mcg, and zinc 2 mg daily may shorten the number of days spent on mechanical ventilation when compared with placebo (61432). It is unclear if these findings are due to manganese, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral intake of or environmental exposure to manganese decreases the risk of metabolic syndrome. Details: A meta-analysis of 12 observational studies suggests that increased dietary intake of manganese or higher levels of manganese in the serum, whole blood, or urine are not associated with a lower risk of metabolic syndrome when compared with lower manganese intake or laboratory values (112138).
• Obesity. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a specific combination product (7-Keto Naturalean, Enzymatic Therapy, Inc.) containing manganese 500 mcg, 7-oxo-DHEA 100 mg, L-tyrosine 100 mg, asparagus root extract 100 mg, choline bitartrate 50 mg, inositol 50 mg, copper gluconate 500 mcg, and potassium iodide 100 mcg daily for 8 weeks reduces body weight by around 1.5 kg and body mass index (BMI) by around 0.7 kg/m² when compared with placebo (61581).
• Osteoarthritis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with osteoarthritis of the knee and lower back show that taking a specific combination product (Cosamin DS, Nutramax Laboratories) containing manganese ascorbate 228-304 mg (about 31-41 mg of elemental manganese), glucosamine hydrochloride 1500-2000 mg, and chondroitin sulfate 1200-1600 mg daily for 4 months improves pain and ability to do activities of daily living when compared with baseline or placebo (4237,7169). The amount of manganese in the Cosamin DS formulation used in this study is considerably higher than the 1 mg of elemental manganese per 1500 mg of glucosamine hydrochloride in the current formulation. Since numerous studies show glucosamine with chondroitin without manganese might be effective for osteoarthritis, it is not possible to draw conclusions about the effects of manganese alone.
• Osteoporosis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal patients shows that taking manganese 5 mg in combination with elemental calcium 1000 mg, zinc 15 mg, and copper 2.5 mg daily for 2 years reduces spinal bone loss when compared with placebo (1994). Another small clinical study in females with osteopenia shows that taking a specific combination product (Vitrum Osteomag, Unipharm Inc.) containing manganese 1.8 mg, calcium 600 mg, vitamin D (cholecalciferol) 200 IU, magnesium 40 mg, zinc 7.5 mg, copper 1 mg, and boron 250 mcg twice daily for one year improves bone mineral density when compared with no treatment (36840). However, since numerous studies have demonstrated the efficacy of calcium plus vitamin D for osteoporosis, it is not possible to draw conclusions about the effects of manganese alone.
• Premenstrual syndrome (PMS). Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with PMS shows that taking manganese 1.0 mg or 5.6 mg in combination with calcium 587 mg or 1336 mg daily for about 24 weeks improves symptoms of PMS including pain, crying, loneliness, anxiety, restlessness, irritability, mood swings, depression, and tension (2004).
• Wound healing. Topical manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research has found that applying an alginate dressing containing manganese, calcium, and zinc to chronic wounds for 12 weeks is associated with improved wound healing when compared with previous treatments (61327). It is unclear if these findings are due to manganese, other ingredients, or the combination. More evidence is needed to rate manganese for these uses.

(Read more about MANGANESE)

LIKELY EFFECTIVE

• Molybdenum deficiency. Taking or consuming molybdenum can treat or prevent molybdenum deficiency (7135,16478). However, molybdenum deficiency is very rare.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Esophageal cancer. Population research suggests that low intake of molybdenum might be associated with an increased risk of esophageal cancer (16478,17205). However, it is not known if molybdenum supplements reduce the risk of developing esophageal cancer. More information is needed to rate molybdenum for this use.

(Read more about MOLYBDENUM)

EFFECTIVE

• Acetaminophen poisoning. Oral and intravenous N-acetyl cysteine, as prescription drug products, are effective for treating acetaminophen poisoning. Details: Administering prescription N-acetyl cysteine orally or intravenously is effective in decreasing mortality rate and preventing the permanent sequelae of acetaminophen poisoning (17,64513,64745,64746). N-acetyl cysteine injection and oral effervescent tablets are approved by the US FDA for this use (102147,104164).
• Atelectasis. When inhaled, N-acetyl cysteine is effective for treating atelectasis. Details: N-acetyl cysteine solution for inhalation is effective for atelectasis caused by mucus obstruction (15,91650) and is approved by the US FDA for this use (102147).
• Bronchial diagnostic studies. When inhaled, N-acetyl cysteine is effective for bronchial diagnostic study preparation. Details: N-acetyl cysteine solution for inhalation is helpful when used to prepare people for bronchial diagnostic studies (15,91650), and is approved by the US FDA for this use (102147).
• Tracheostomy care. When inhaled and used as adjunct therapy, N-acetyl cysteine is effective for preventing endotracheal crusting in patients with a tracheostomy. Details: N-acetyl cysteine solution for inhalation is effective when used as an adjunct for preventing endotracheal crusting in tracheostomy care (15), and is approved by the US FDA for this use (102147).

POSSIBLY EFFECTIVE

• Angina. Oral or intravenous N-acetyl cysteine may reduce nitroglycerin tolerance in patients with angina. However, some studies suggest that N-acetyl cysteine might increase the risk for severe headaches and hypotension when used with intravenous or transdermal nitroglycerin. Details: Administering N-acetyl cysteine orally or intravenously, in combination with nitroglycerin, seems to improve unstable angina pectoris (2245,2246). There is also some clinical research showing that concurrent intravenous or oral administration of N-acetyl cysteine reduces the development of nitroglycerin tolerance (832,2245,64546). However, other research shows that taking N-acetyl cysteine orally does not reduce the development of nitroglycerin tolerance in angina patients (2281,2282). Additionally, severe headache and hypotension can occur when oral N-acetyl cysteine and nitroglycerin are administered together, which may limit the feasibility of concomitant use (2245).
• Autism spectrum disorder. Oral N-acetyl cysteine may improve irritability, but not other symptoms, associated with autism spectrum disorder. Details: One small clinical study in children with autism shows that taking N-acetyl cysteine 900 mg daily for 4 weeks followed by 900 mg twice daily for 4 weeks and then 900 mg three times daily for 4 weeks improves symptoms of irritability when compared with placebo (91241). Another small clinical study in children and adolescents with autism shows that taking N-acetyl cysteine 1200 mg daily plus risperidone for 8 weeks is more effective than risperidone alone for reducing irritability (91239). However, it does not seem to improve other symptoms, such as hyperactivity, social withdrawal, lethargy, repetitive behaviors, and inappropriate speech (91239,91241,97047).
• Bronchitis. Via inhalation, N-acetyl cysteine is FDA-approved for managing acute episodes of bronchitis. Oral N-acetyl cysteine may help to reduce the occurrence of acute exacerbations of chronic bronchitis when used for 3-36 months. Details: N-acetyl cysteine solution for inhalation is FDA-approved for the management of acute bronchopulmonary disease, including bronchitis (102147). Taking N-acetyl cysteine 1200-1500 mg daily orally for 4 months seems to reduce shortness of breath and coughing, and improve lung capacity, in patients with sulfur mustard-induced bronchitis (64586,64614). Also, taking N-acetyl cysteine orally, usually 400-600 mg daily, seems to reduce the risk of acute exacerbations of chronic bronchitis by a moderate amount when used for 3-36 months (6176,64419,102660). Symptom improvement has been shown to occur in 61% of patients taking N-acetyl cysteine, compared with 34% of those taking placebo (102660). However, oral N-acetyl cysteine does not seem to have a beneficial effect on chronic bronchitis when administered for shorter durations (64685,64696,64737,64818).
• Chronic obstructive pulmonary disease (COPD). Taking N-acetyl cysteine orally seems to decrease the exacerbation rate and improve symptoms in patients with moderate to severe COPD, particularly those who are not taking inhaled corticosteroids. Also, taking N-acetyl cysteine along with standard therapy appears to improve recovery in patients hospitalized due to an acute exacerbation. Details: N-acetyl cysteine solution for inhalation is FDA-approved for the management of chronic bronchopulmonary disease, such as COPD (102147). A meta-analysis of 12 clinical studies involving 2,691 patients shows that N-acetyl cysteine, given as 257-1800 mg daily for at least 6 months, decreases the number of patients experiencing at least one COPD exacerbation by 15% when compared with placebo; however, it is not associated with a reduction in COPD exacerbation rate or improvement in measures of lung function (97046). Some smaller studies have shown a higher improvement rate of 23% to 40%, with the greatest efficacy seen in patients who are not already taking inhaled corticosteroids (10429,64552). While some studies have failed to show any benefit of N-acetyl cysteine, the lack of benefit appears to correlate with a treatment duration of less than 6 months (64704,97039,97046). The 2015 guidelines from the American College of Chest Physicians and Canadian Thoracic Society (AECOPD) recommend that N-acetyl cysteine be considered as an adjunctive treatment option for patients with moderate to severe COPD and a history of 2 or more exacerbations in the previous 2 years (97043). The 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline also states that N-acetyl cysteine may be an appropriate treatment option for patients who are not able to use inhaled corticosteroids (97050). In hospitalized patients with an acute exacerbation of COPD, preliminary clinical research shows that adding N-acetyl cysteine 1200 mg daily to regular treatment has a moderate effect on wheeze and the need for oxygen over a 7-day period when compared with regular treatment alone (102653).
• Contrast induced nephropathy. Oral or intravenous administration of N-acetyl cysteine seems to prevent contrast induced nephropathy in patients with kidney dysfunction. However, it is not beneficial in those with normal kidney function or diabetes. Details: Large meta-analyses of over 150 clinical studies in patients with reduced kidney function (serum creatinine of 1.2-2.4 mg/dL) show that oral N-acetyl cysteine is more effective than either sodium bicarbonate or saline hydration alone in preventing contrast agent-induced kidney damage after coronary angiography, computed tomography, left heart catheterization, and/or percutaneous coronary intervention. N-acetyl cysteine in combination with sodium bicarbonate appears to have similar efficacy to N-acetyl cysteine monotherapy, with an odds ratio of 0.62-0.67, when compared with hydration alone. Pretreatment with high-dose statin, prostaglandin, or theophylline appears to be more effective than N-acetyl cysteine, with odds ratios of 0.37, 0.37, and 0.48, respectively, when compared with hydration alone. However, combination treatment with N-acetyl cysteine and a high-dose statin appears to provide the greatest benefit of all treatments studied, with an odds ratio of 0.31, when compared with hydration alone. No treatments demonstrate significant efficacy in reducing the risk of contrast induced nephropathy in patients with diabetes (97036,97038). Some evidence also suggests that N-acetyl cysteine may have similar effects to fenoldopam in reducing the risk of contrast induced nephropathy in patients with reduced kidney function (64489,97036,97038). N-acetyl cysteine does not reduce the risk of contrast induced nephropathy in patients with normal kidney function (mean serum creatinine less than 1.2 mg/dL) when compared with control (64538,64573,64617). Although many individual studies have failed to show a significant benefit (11430,64514,64543,64561,64581,64623,64639,91232,91236,106884), pooled evidence from these and many additional studies provide a benchmark for the place for N-acetyl cysteine in reducing the risk of contrast induced kidney damage in people with reduced kidney function.
• Hyperhomocysteinemia. Oral N-acetyl cysteine seems to reduce homocysteine levels. Details: Taking N-acetyl cysteine orally seems to reduce homocysteine levels in patients with elevated homocysteine levels, including those with kidney failure requiring dialysis (2258,64542,64596).
• Hyperlipidemia. Oral N-acetyl cysteine seems to reduce lipoprotein(a) levels. Details: Taking N-acetyl cysteine orally seems to modestly reduce lipoprotein(a) levels in patients with hyperlipidemia (2256,2257,64516).
• Ifosfamide (Ifex) toxicity. Oral N-acetyl cysteine may be beneficial for reducing ifosfamide toxicity, although it does not appear to be as effective as mesna. Details: Taking N-acetyl cysteine orally seems to reduce ifosfamide-induced bladder toxicity (5808,10270,64730). However, mesna seems to be more effective for preventing ifosfamide toxicity than N-acetyl cysteine (10748).
• Influenza. Oral N-acetyl cysteine may reduce the risk for symptomatic influenza. Details: One multi-center clinical trial conducted in Italy shows that taking N-acetyl cysteine 600 mg twice daily for 6 months does not prevent influenza infection, but reduces the risk for clinically apparent disease by 68%, when compared with placebo (2260).
• Kidney failure. Oral N-acetyl cysteine may reduce the risk for cardiovascular events in patients with kidney failure. Details: One clinical study in adults with kidney failure who have been on dialysis for at least 3 months shows that taking N-acetyl cysteine 600 mg twice daily reduces the incidence of cardiovascular events, such as ischemic stroke and myocardial infarction, by about 40% when compared with placebo. There was no effect on total mortality or mortality from cardiovascular causes, although the study may have been inadequately powered to detect a difference in these outcomes (10430).
• Myocardial infarction (MI). Intravenous N-acetyl cysteine, along with standard therapy, seems to improve outcomes in patients with MI. Oral N-acetyl cysteine has not been evaluated for this use. Details: Clinical research in adults undergoing percutaneous coronary intervention (PCI) for ST-segment elevation MI shows that administering N-acetyl cysteine with nitroglycerin as a continuous intravenous infusion for 48 hours reduces myocardial infarct size by 5.5%, doubles the extent of myocardial salvage, and shortens the time to chest pain resolution when compared with nitroglycerin plus placebo (97044). Additional preliminary clinical research shows that intravenous N-acetyl cysteine, when given with nitroglycerin and streptokinase in patients with evolving MI, may preserve left ventricular function and reduce oxidative stress (7872,64502,64778).

POSSIBLY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Subcutaneous administration of N-acetyl cysteine does not seem to improve survival or disease progression in patients with ALS. Details: One clinical trial in patients with ALS shows that administering N-acetyl cysteine 50 mg/kg daily for 12 months via subcutaneous injection does not improve survival or slow disease progression when compared with placebo (2254).
• Anthracycline cardiotoxicity. Oral N-acetyl cysteine does not seem to prevent or treat doxorubicin-induced cardiac toxicity. Details: Small clinical studies show that taking N-acetyl cysteine orally does not seem to prevent or reverse doxorubicin-induced cardiac toxicity when compared with placebo or a control group (2252,2253,64712).
• Bronchopulmonary dysplasia. Intratracheal N-acetyl cysteine does not seem to prevent bronchopulmonary dysplasia in premature infants. Details: Clinical research in premature infants shows that intratracheal N-acetyl cysteine does not seem to improve symptoms, hasten recovery of chronic lung disease, or reduce the risk of bronchopulmonary dysplasia when compared with placebo (64460,64490).
• Cannabis use disorder. Oral N-acetyl cysteine does not seem to improve abstinence rates in patients with cannabis use disorder. Details: Most clinical research in adolescents and adults with cannabis use disorder shows that taking N-acetyl cysteine 1200 mg twice daily for 8-12 weeks as an adjunct to counseling and other interventions does not reduce symptoms of depression or help with cannabis abstinence (99531,102663,102666,102668). Although a single study shows that taking N-acetyl cysteine more than doubles the odds of a negative urine cannabinoid test over an 8-week period in adolescents aged 15-21 when compared with placebo, there was no significant difference in the time to first negative urine cannabinoid test or end of treatment abstinence (102666).
• Cystic fibrosis. Oral or inhaled N-acetyl cysteine does not seem to improve lung function in patients with cystic fibrosis. Details: Most clinical research shows that taking oral or nebulized N-acetyl cysteine does not significantly improve lung function or lung capacity in patients with cystic fibrosis when compared with a control (22735,64406,64671,64743). However, one preliminary clinical study shows that high-dose oral N-acetyl cysteine reduces the number and activity of airway neutrophils in these patients when compared with placebo (64510).
• Erythropoietic protoporphyria (EPP). Oral N-acetyl cysteine does not seem to improve photosensitivity in patients with EPP. Details: Small clinical studies show that taking N-acetyl cysteine 1800 mg daily orally for 4 weeks does not improve photosensitivity in patients with EPP when compared with placebo or baseline (64448,64756).
• Helicobacter pylori. Adding oral N-acetyl cysteine to conventional Helicobacter pylori (H. pylori) eradication regimens does not seem to increase eradication rates. Details: Despite conflicting findings from individual, small clinical studies (64497,97042), meta-analyses of clinical research show that adding N-acetyl cysteine to a standard antibiotic eradication regimen does not improve eradication when compared with standard eradication therapy alone (99530,106901). N-acetyl cysteine has also been evaluated in combination with other ingredients. Preliminary clinical research shows that taking N-acetyl cysteine 600 mg orally twice daily in combination with curcumin 30 mg, bovine lactoferrin 100 mg, and pantoprazole 20 mg, all taken twice daily for one week, without antibiotic therapy does not eradicate H. pylori infection, although it might improve dyspeptic symptoms and gastrointestinal inflammation (64559).
• Hepatitis. Oral N-acetyl cysteine does not appear to improve treatment response in patients with hepatitis. However, when taken with interferon, it might lengthen the time to relapse. Details: Taking N-acetyl cysteine orally does not seem to benefit patients with acute viral hepatitis (64462). Also, adding N-acetyl cysteine to conventional interferon therapy does not seem to improve treatment response in patients with hepatitis C when compared with interferon therapy alone (64418,64799,64825). However, some clinical research shows that adding N-acetyl cysteine to interferon therapy delays relapse in hepatitis C patients when compared with interferon treatment alone (64424).
• HIV/AIDS. Oral N-acetyl cysteine does not seem to increase CD4+ cell count in patients with HIV. Details: Small clinical studies show that taking N-acetyl cysteine 400 mg orally twice daily or 600 mg once daily for 4-6 months does not improve CD4+ cell counts or viral load in patients with HIV when compared with placebo (64482,64779). In addition, taking N-acetyl cysteine 600 mg orally three times daily in combination with sodium selenite 500 mcg daily for up to 24 weeks does not affect the percentage of CD4+ lymphocytes or viral load in HIV patients when compared with a control (64798).
• Hypotension. Oral N-acetyl cysteine does not seem to improve renal outcomes in patients with prolonged hypotension. Details: One clinical trial in patients with prolonged hypotension shows that taking N-acetyl cysteine orally for 7 days does not reduce the risk of acute kidney failure when compared with placebo (64545).
• Infertility. Oral N-acetyl cysteine does not seem to improve fertility in females with unexplained infertility. Details: One clinical trial in females with unexplained infertility shows that taking oral N-acetyl cysteine 1200 mg daily in addition to clomiphene citrate 50 mg twice daily for 5 days, beginning on the second day of the cycle, does not improve pregnancy rate or reduce miscarriage rate when compared with clomiphene citrate alone (64528).
• Liver transplant. Intravenous N-acetyl cysteine during liver donor operation does not seem to improve liver transplant outcomes. Oral N-acetyl cysteine has not been evaluated for this use. Details: One clinical trial shows that administering N-acetyl cysteine intravenously during a liver donor operation and preserving the liver in cold solution containing N-acetyl cysteine does not reduce the risk of ischemia reperfusion injury or acute cellular rejection in liver transplant recipients when compared with control (64486).
• Pancreatitis. Oral N-acetyl cysteine does not seem to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Additionally, intravenous N-acetyl cysteine does not seem to reduce the risk of organ dysfunction in patients being treated for severe acute pancreatitis. Details: Two clinical trials show that taking oral N-acetyl cysteine 1200 mg once before undergoing ERCP does not reduce the risk of post-ERCP pancreatitis when compared with placebo (64522,109939). One of these trials also evaluated oral N-acetyl cysteine in combination with rectal indomethacin, but the incidence of post-ERCP pancreatitis did not appear to be lower when compared with taking indomethacin alone. However, the study may have been inadequately powered to detect a difference between those groups (109939). In patients with severe acute pancreatitis, intravenous N-acetyl cysteine, in combination with selenium and vitamin C, also does not seem to reduce the risk of organ dysfunction (64551).
• Postoperative recovery. Oral or intravenous N-acetyl cysteine does not seem to improve survival, prevent complications, or reduce length of hospital stay in patients undergoing cardiac or liver surgery. Details: N-acetyl cysteine, taken orally or intravenously, does not seem to reduce the risk of myocardial infarction, stroke, kidney injury, or mortality or reduce the length of hospital stay following cardiac surgery (64610,64624,64628,64635,91233,91240). While some meta-analyses of clinical research show that taking N-acetyl cysteine orally or intravenously reduces the odds of postoperative atrial fibrillation by 36% to 44% when compared with placebo in patients undergoing cardiac surgery (64635,91233,91240), conflicting results exist (64624). In patients undergoing liver resection, intravenous N-acetyl cysteine does not reduce complication rate, risk of liver failure, length of hospital stay, or mortality when compared with a control group. In fact, patients receiving N-acetyl cysteine were more likely to experience delirium and its associated complications (99532).

LIKELY INEFFECTIVE

• Head and neck cancer. Oral N-acetyl cysteine does not seem to reduce mortality, improve event-free survival, or prevent additional tumors in patients with head and neck cancer. Details: Taking N-acetyl cysteine orally does not prevent second primary tumors in patients with head and neck cancer (1710). Also, N-acetyl cysteine alone, or in combination with retinyl palmitate, has no effect on mortality or event-free survival in these patients (1710).
• Lung cancer. Oral N-acetyl cysteine does not seem to reduce mortality, improve event-free survival, or prevent additional tumors in patients with lung cancer. Details: Taking N-acetyl cysteine orally does not prevent second primary tumors in patients with lung cancer (1710). Also, N-acetyl cysteine alone, or in combination with retinyl palmitate, has no effect on mortality or event-free survival in these patients (1705,1710).
• Multisystem organ failure. Administering intravenous N-acetyl cysteine might increase the risk of mortality due to multisystem organ failure. Oral N-acetyl cysteine has not been evaluated for this use. Details: Administering N-acetyl cysteine intravenously, greater than 24 hours after hospital admission, might increase mortality rate due to multisystem organ failure. The effect of N-acetyl cysteine given within 24 hours of hospital admission requires further study (7871).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Research on the use of intravenous N-acetyl cysteine in patients with ARDS is conflicting. Oral N-acetyl cysteine has not been evaluated for this purpose. Details: Some clinical research shows that N-acetyl cysteine might reduce mortality and improve oxygenation in patients with acute lung injury/ARDS when compared with a control (64619). These patients were administered intravenous N-acetyl cysteine 150 mg/kg on the first day followed by 50 mg/kg for 3 more days. However, other clinical research shows that administering intravenous N-acetyl cysteine 40 mg/kg daily for 3 days does not reduce the risk of ARDS development in patients with acute lung injury (64771). Also, some clinical research shows that intravenous N-acetyl cysteine for up to 6 days does not reduce the time for improvement in patients with ARDS (64492). These discrepancies may be due to variations in genes involved in glutathione-S-transferase (GST) expression (64619).
• Adrenoleukodystrophy (ALD). It is unclear if oral or intravenous N-acetyl cysteine is beneficial in patients with ALD. Details: A case series of three male children with this rare condition suggests that administering N-acetyl cysteine orally and intravenously might improve overall survival and stabilize neurologic status after hematopoietic stem cell transplantation when compared with historical controls (64547).
• Aging. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults shows that taking a combination product containing N-acetyl cysteine 100 mg/kg, glycerine 100 mg/kg, and alanine 200 mg/kg orally daily for 16 weeks modestly improved waist circumference, systolic blood pressure, and some serum markers of oxidative stress, but not body-mass index or diastolic blood pressure, when compared with placebo (110624). It is unclear if this effect is due to N-acetyl cysteine, other ingredients, or the combination.
• Alcohol-related liver disease. Although there has been interest in using oral N-acetyl cysteine for preventing alcohol-related liver damage, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral N-acetyl cysteine for allergic rhinitis, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this condition.
• Altitude sickness. It is unclear if oral N-acetyl cysteine can treat or prevent altitude sickness. Details: One very small clinical trial shows that taking N-acetyl cysteine 400 mg daily does not reduce altitude-associated anorexia or improve food intake in individuals exposed to high altitudes when compared with either placebo or vitamin E 400 mg daily (64599).
• Alzheimer disease. It is unclear if oral N-acetyl cysteine is beneficial for Alzheimer disease. Details: One clinical trial in a small number of patients with Alzheimer disease shows that taking N-acetyl cysteine 50 mg/kg daily for 6 months does not improve most cognitive symptoms of Alzheimer disease when compared with placebo (7870). However, preliminary clinical research in adults with mild to moderate Alzheimer disease also shows that taking a combination product containing N-acetyl cysteine 2.55 grams, L-serine 12.35 grams, nicotinamide riboside 1 gram, and L-carnitine tartrate 3.73 grams orally once daily for 28 days followed by twice daily for 56 more days improves cognitive functioning scores by 14% to 29% when compared with placebo (110623). It is unclear if this effect is due to N-acetyl cysteine, other ingredients, or the combination.
• Aminoglycoside ototoxicity. Small clinical studies suggest that oral N-acetyl cysteine may modestly reduce the risk of ototoxicity caused by aminoglycoside therapy. Details: A meta-analysis of available clinical research in adults with kidney failure receiving aminoglycosides for bloodstream infections shows that taking N-acetyl cysteine 600 mg twice daily for a total of 14 days, or for up to 7 days after completion of aminoglycoside therapy, reduces the risk of hearing loss by 33% when compared with placebo. The findings of this analysis are limited by the small sample sizes and high risk of bias of the included studies (97049).
• Asthma. It is unclear if inhaling N-acetyl cysteine is beneficial in patients with asthma. Details: Preliminary clinical research shows that, when administered as an aerosol daily for one week in combination with isoproterenol, N-acetyl cysteine 10% improves lung capacity and decreases sputum viscosity when compared with placebo in patients with asthma (64674).
• Athletic performance. It is unclear if oral N-acetyl cysteine can improve athletic performance. Details: Some small clinical studies shows that N-acetyl cysteine might be beneficial if taken orally at a dose of 1200 mg daily for 9 days leading up to exercise or when administered intravenously both before and during exercise (64529,91248), but that it might not improve performance when taken as a single 20 mg/kg oral dose 60 minutes prior to exercise (102028).
• Biliary disorders. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with biliary disorders. Oral N-acetyl cysteine has not been evaluated for this use. Details: Preliminary clinical research in patients undergoing surgical bypass for obstructive jaundice shows that postoperative intravenous N-acetyl cysteine for 48 hours reduces levels of some liver enzymes, but not bilirubin levels or mean hospital stay, when compared with a control group. Although all liver enzyme levels had not returned to normal by 30 days after surgery, they were more improved in the group using N-acetylcysteine (102654).
• Bipolar disorder. The effects of oral N-acetyl cysteine in patients with bipolar disorder are conflicting. Oral N-acetyl cysteine might reduce symptoms of depression and increase remission rates, but it does not appear to be beneficial for reducing symptoms of mania or for maintaining remission. Details: One clinical study in patients with bipolar disorder shows that taking N-acetyl cysteine 1000 mg twice daily as adjunct to usual therapy for 24 weeks reduces symptoms of depression when compared with placebo (64608). A subgroup analysis of patients from this study who were diagnosed with bipolar II disorder shows that this dose of N-acetyl cysteine can increase the number of patients who achieve remission of both depression and mania, but not the number achieving remission of only one of these, when compared with placebo (91243). However, other research shows that taking N-acetyl cysteine 3 grams daily in addition to standard therapy for 20 weeks does not improve depression when compared with placebo in patients with bipolar depression experiencing a depressive episode for at least 4 weeks. A limitation of this study is the high (56%) placebo response rate, which might have limited the ability to detect between-group differences in symptoms improvements (99529). Taking N-acetyl cysteine as an adjunct to usual therapy does not appear to be beneficial for maintaining remission. A clinical study in patients with bipolar disorder shows that, although taking N-acetyl cysteine 1000 mg twice daily for 8 weeks improves symptoms of bipolar disorder when compared to baseline, maintenance therapy with N-acetyl cysteine for an additional 6 months does not improve depression symptoms or prevent recurrence when compared with placebo (91234).
• Bronchiectasis. Oral N-acetyl cysteine has been evaluated in patients with bronchiectasis, with promising results. Details: Preliminary clinical research in Chinese adults with bronchiectasis shows that taking N-acetyl cysteine 600 mg twice daily for 12 months reduces the risk of exacerbation by 59% when compared with a control group receiving on-demand treatment only. For every eight patients treated with N-acetyl cysteine, one additional patient was free of exacerbations at 12 months when compared with on-demand treatment only (102027).
• Canker sores. It is unclear if rinsing the mouth with N-acetyl cysteine solution is beneficial in patients with canker sores. Details: Preliminary clinical research in patients with recurrent canker sores shows that rinsing the mouth with N-acetyl cysteine (ACC, HEXAL AG) 200 mg dissolved in water for 30 seconds is no more effective than 0.12% chlorhexidine digluconate for canker sore healing time or level of pain. However, pain was reduced by 50% to 90% more over baseline 2-4 days after use of N-acetyl cysteine when compared with 0.12% chlorhexidine digluconate (102659).
• Chemotherapy-induced hepatotoxicity. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with chemotherapy-induced hepatotoxicity. Oral N-acetyl cysteine has not been evaluated for this use. Details: Some observational research in children aged 2-17 years with chemotherapy-induced hepatotoxicity has found that intravenous N-acetyl cysteine 3 mcg/kg over 24 hours is associated with day-to-day improvement in liver injury, based on liver function enzyme levels, when compared with no N-acetyl cysteine therapy. Decreases in liver enzymes also occurred earlier in patients using N-acetyl cysteine (102664).
• Chemotherapy-induced peripheral neuropathy. Small clinical studies suggest that oral N-acetyl cysteine may reduce the risk for peripheral neuropathy in patients receiving oxaliplatin. Details: One preliminary clinical study in patients with colon cancer shows that taking N-acetyl cysteine 1200 mg orally at 1.5 hours prior to oxaliplatin therapy reduces the incidence of oxaliplatin-induced neuropathy when compared with placebo (64505). Another small clinical trial in patients with gastric or colorectal cancers shows that taking N-acetyl cysteine (Osveh Pharmaceutical Company) 1200 mg one hour before receiving oxaliplatin during eight courses of chemotherapy reduces the incidence and severity of neurotoxicity symptoms when compared with placebo. In patients taking N-acetyl cysteine, 31% had no signs of neurotoxicity after oxaliplatin chemotherapy, compared with 0% of those taking placebo. Also, 44% had mild symptoms, compared with 6% of those taking placebo. However, there were no significant differences in electrophysiological sensory results (102665).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral N-acetyl cysteine for CFS, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Chronic kidney disease (CKD). Oral N-acetyl cysteine does not seem to improve kidney function in patients with CKD or reduce the risk of kidney injury or other complications after cardiac surgery in patients with CKD. However, intravenous N-acetyl cysteine might offer some benefit in patients with CKD undergoing cardiac surgery. Details: Clinical research shows that taking N-acetyl cysteine 1200 mg orally daily in combination with standard antihypertensive drugs does not reduce proteinuria or other markers of kidney injury in patients with CKD (64627). N-acetyl cysteine has also been evaluated for the prevention of acute kidney injury following cardiac surgery in patients with CKD, with conflicting results. Several meta-analyses have shown that N-acetyl cysteine does not reduce the incidence of acute kidney injury, postoperative complications, postoperative interventions, length of hospitalization, or mortality after cardiac surgery in adults with CKD (95766,95767,95768). However, these meta-analyses found that intravenous, but not oral, N-acetyl cysteine might be beneficial (95767,95768). A more recent meta-analysis shows that intravenous N-acetyl cysteine reduces the risk of postoperative acute kidney injury by 23% and reduces the risk of cardiac adverse events by 17% (99533). However, most of the studies included in this latter meta-analysis were small and the definition of cardiac events varied among the included studies. Higher quality research is needed to determine the benefit, if any, of N-acetyl cysteine in reducing acute kidney injury after cardiac surgery in patients with CKD.
• Cocaine dependence. It is unclear if oral N-acetyl cysteine is effective for reducing cravings or withdrawal symptoms in people trying to stop cocaine use. Details: Some preliminary clinical research shows that taking N-acetyl cysteine 600 mg twice daily for 2 days reduces the desire to use cocaine when compared with placebo in individuals with cocaine dependence (64563). However, other preliminary clinical research shows that taking oral N-acetyl cysteine 600 mg twice daily for 2 days does not reduce cravings or withdrawal symptoms when compared with placebo in patients hospitalized for cocaine dependency (64504).
• Colorectal cancer. It is unclear if oral N-acetyl cysteine is effective for preventing colorectal cancer. Details: Clinical research in a small group of patients with a history of adenomatous colonic polyps shows that taking N-acetyl cysteine 800 mg daily for 12 weeks reduces the proliferative index of colonic crypts, suggesting that N-acetyl cysteine might decrease the likelihood of colorectal cancer (7873).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral or intravenous N-acetyl cysteine is beneficial in patients undergoing CABG surgery. Details: A small clinical study shows that taking N-acetyl cysteine 300 mg orally in addition to intermittent blood cardioplegia does not affect postoperative outcomes or the risk of mortality when compared with control in patients undergoing elective CABG surgery (64638). Another small clinical study shows that giving N-acetyl cysteine 100 mg/kg by intravenous infusion, for two doses during CABG surgery and one postoperative dose, seems to reduce serum creatinine levels at 4 and 48 hours after surgery and reduce the incidence of acute kidney injury when compared with placebo. However, serum creatinine levels were within the normal range in all patients (106886).
• Coronavirus disease 2019 (COVID-19). Small clinical trials suggest that intravenous N-acetyl cysteine is not beneficial in patients at risk for respiratory failure from severe COVID-19. It is unclear if oral use is beneficial. Details: A small single-center clinical trial of patients presenting to the emergency room with COVID-19 pneumonia in Brazil shows that receiving intravenous N-acetyl cysteine 21 grams in dextrose 5% over 20 hours in conjunction with institutional standard care, including empiric antibiotics, does not reduce the need for mechanical ventilation, length of intensive care unit (ICU) stay, or mortality when compared with dextrose 5% (105560). Another small single-center clinical trial in patients with COVID-19 and acute respiratory distress syndrome (ARDS) in Iran shows that receiving a continuous intravenous infusion of N-acetyl cysteine 40 mg/kg in dextrose 5% daily for 3 days in conjunction with institutional standard care, including corticosteroids, vitamin C, vitamin D, and zinc, also does not reduce the need for mechanical ventilation, length of ICU stay, or mortality when compared with dextrose 5% (105561). Similarly, a retrospective study of patients hospitalized in Italy for COVID-19 pneumonia shows that receiving intravenous N-acetyl cysteine 300 mg three times daily, switched to 600 mg twice daily if the patient was clinically stable, for a duration of least 5 days, does not improve inpatient mortality, ICU admission, length of ICU stay, or the incidence of atelectasis, when compared with no supplementation. At a 6-month follow-up, treatment with N-acetyl cysteine also did not appear to impact long-term outcomes in these patients (108449). In contrast, a small, retrospective study in hospitalized patients with moderate to severe COVID-19 pneumonia shows that taking oral N-acetyl cysteine, 600 mg twice daily for 10 days in addition to standard care, including empiric antibiotics, corticosteroids, and remdesivir, reduces the risk for severe respiratory failure requiring ventilator support and reduces mortality at 14 days in those with severe pneumonia when compared with standard care alone (106885). Prospective, randomized, double-blind trials are needed to confirm these findings.
• Dental plaque. It is unclear if mouthwash solutions containing N-acetyl cysteine can reduce dental plaque; higher concentrations may be more effective than lower concentrations. Details: Preliminary clinical research shows that using a mouthwash solution containing N-acetyl cysteine 10% four times daily for 7 days reduces dental plaque (64687). However, other clinical research shows that rinsing twice daily for 3 weeks with N-acetyl cysteine 1.25% does not reduce the development of plaque. In addition, N-acetyl cysteine 1.25% was not beneficial when used for 2 weeks as a treatment for experimental plaque (102662).
• Dry eye. Small clinical studies suggest that eye drops containing N-acetyl cysteine, with or without chitosan, might improve objective measures of dry eye. Details: Preliminary clinical research in patients with dry eye shows that using tear solution containing 20% N-acetyl cysteine every two hours for 2 months improves objective, but not subjective, symptoms of dry eye syndrome when compared with artificial tears (64705). A small clinical study in patients with moderate to severe dry eye disease shows that applying a specific product (Lacrimera) containing chitosan-N-acetyl cysteine as one drop once or twice daily improves tear film thickness (TFT) after 10 minutes of application, and is maintained for 24 hours, when compared with placebo. Once or twice daily application does not seem to alter the level of benefit (97710). It is unclear if the benefit of this combination product is due to N-acetyl cysteine, chitosan, or the combination.
• Endometriosis. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with endometriosis-associated pelvic pain shows that taking a combination product containing N-acetyl cysteine 1200 mg, alpha lipoic acid 400 mg, bromelain 50 mg, and zinc 20 mg daily for 6 months improves pain and reduces analgesic intake when compared to baseline (99535). This study was limited by a lack of comparator group.
• Esophagogastroduodenoscopy (EGD). It is unclear if N-acetyl cysteine (NAC) can improve visualization when used as a premedication for EGD. Details: Clinical research shows that giving NAC orally, 600 mg in 90 mL of an emulsion formulation, 20 minutes prior to EGD reduces foaming and mucus, allowing better visualization of the mucosa. The percentage of patients with no bubbles affecting visualization is about 51% with NAC, compared with 34% with placebo. The percentage not requiring suction or endoscopic flushes is 50% with NAC and 27% with placebo. Giving simethicone 150 mg in combination with NAC further improves visualization (108941).
• Exercise-induced muscle damage. It is unclear if oral N-acetyl cysteine is effective for preventing or treating exercise-induced muscle damage. Details: One small clinical study shows that taking N-acetyl cysteine 20 mg/kg daily in three divided doses after muscle-damaging exercise does not improve muscle repair or inflammatory response in healthy patients taking part in a specific resistance training program (91244).
• Fibrocystic breast disease. It is unclear if oral N-acetyl cysteine is effective for fibrocystic beast disease. Details: Preliminary clinical research in adult females with fibrocystic breast disease and cyclical mastalgia shows that taking N-acetyl cysteine (Osvah Pharmaceutical Company) 600 mg orally once daily for 12 weeks modestly improves pain scores when compared with placebo (109938).
• Gingivitis. It is unclear if mouthwash containing N-acetyl cysteine is effective for the prevention or treatment of gingivitis. Details: Clinical research shows that rinsing twice daily for 3 weeks with N-acetyl cysteine 1.25% is slightly more effective than placebo for reducing the development of gingivitis. However, there was no effect on plaque. In addition, N-acetyl cysteine is not as effective as chlorhexidine 0.2% and had no benefit when used for 2 weeks as a treatment for experimental gingivitis (102662).
• Hangover. Although there has been interest in using oral N-acetyl cysteine for treating hangovers, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Hearing loss. It is unclear if oral N-acetyl cysteine is effective for preventing or treating hearing loss. Details: A meta-analysis of clinical trials in adults shows that taking N-acetyl cysteine 900-2700 mg orally daily for up to 42 days modestly protects against noise-induced hearing loss in middle to high hearing thresholds (0 to 4 kHz and 0 to 6 kHz), but not low hearing thresholds (0 to 2 kHz), when compared with control. However, the validity of this study is limited by high heterogeneity (109937). Another meta-analysis of 2 clinical trials in adults with sudden hearing loss shows that taking N-acetyl cysteine 1200 mg orally daily for 2 weeks to 3 months moderately improves pure tone threshold hearing when compared with control (109940).
• Hepatorenal syndrome. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with hepatorenal syndrome. Oral N-acetyl cysteine has not been evaluated for this use. Details: A case series of 12 patients with hepatorenal syndrome reported that intravenous N-acetyl cysteine, starting with a 150 mg/kg loading dose over 2 hours, followed by a continuous infusion of 100 mg/kg daily for 5 days, modestly improved kidney function, but not liver function or blood pressure. When compared with historical controls, N-acetyl cysteine administration was also associated with an improvement in total survival time (1752). Prospective clinical studies are needed to confirm these findings.
• Hereditary hemorrhagic telangiectasia (HHT). It is unclear if oral N-acetyl cysteine is beneficial in patients with HHT. Details: One small clinical study shows that taking N-acetyl cysteine 600 mg three times daily orally for 12 weeks decreases the frequency and severity of daytime nosebleeds, but not nighttime nosebleeds, when compared to baseline in individuals with HHT (64643). The validity of these findings is limited by the lack of a comparator group.
• Idiopathic interstitial pneumonia. It is unclear if oral or inhaled N-acetyl cysteine is beneficial for the management of various forms of interstitial pneumonia. Details: A very small clinical study in patients with idiopathic interstitial pneumonia shows that taking N-acetyl cysteine 600 mg three times daily for 12 weeks seems to improve pulmonary function tests and decrease biochemical markers of disease when compared with baseline (7868). However, a meta-analysis of clinical research in patients with idiopathic pulmonary fibrosis, a specific type of interstitial pneumonia, shows that oral or inhaled N-acetyl cysteine does not reduce the risk of acute exacerbations or attenuate decline of lung function as measured by forced vital capacity (FVC), when compared with placebo (99538).
• Lead toxicity. Although there has been interest in using oral N-acetyl cysteine for lead toxicity, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Malaria. It is unclear if intravenous N-acetyl cysteine is beneficial as an adjunct in treating malaria. Oral N-acetyl cysteine has not been evaluated for this use. Details: One small clinical study shows that intravenous N-acetyl cysteine, in combination with intravenous artesunate, does not reduce symptoms or the risk of mortality in patients with severe malaria when compared with artesunate alone (64630).
• Male infertility. It is unclear of oral N-acetyl cysteine is beneficial for male infertility. Details: Clinical research in adults with idiopathic oligoasthenoteratospermia shows that taking N-acetyl cysteine 600 mg orally daily for 26 weeks improves sperm concentration, but not sperm motility, when compared with placebo (64626). Additionally, a preliminary clinical study in adults with asthenoteratozoospermia shows that taking N-acetyl cysteine 600 mg daily for 3 months improves sperm motility and concentration, increases protamine, and improves hormone levels and sperm morphology when compared to baseline (99534). The validity of this study is limited by the lack of a comparator group. There is also interest in using N-acetyl cysteine to attenuate the infertility effects observed after COVID-19 infection. A large clinical study in males who had normal sperm analysis prior to COVID-19, but with significantly lower sperm parameters within 6 weeks after infection, shows that taking oral N-acetyl cysteine 600 mg daily for 3 months improves sperm volume, concentration, morphology, and total motility when compared with baseline post-COVID-19 levels (108447). Although the study enrolled a control group, the investigators did not provide a statistical comparison of outcomes between groups, limiting the validity of this finding.
• Mercury toxicity. Although there has been interest in using oral N-acetyl cysteine for mercury toxicity, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Miscarriage. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its benefit when used alone is unclear. Details: One small clinical trial shows that taking oral N-acetyl cysteine 600 mg daily with folic acid 500 mcg daily improves the likelihood of maintaining pregnancy past 20 weeks when compared with folic acid alone in adults with a history of recurrent pregnancy loss (64616).
• Multiple sclerosis (MS). It is unclear if oral and intravenous N-acetyl cysteine are beneficial in patients with MS. Details: One clinical trial in a small group of patients with MS shows that intravenous and oral N-acetyl cysteine in addition to standard care for 2 months improves self-reported cognition by a moderate amount when compared with standard care alone. Self-reported attention also seems to improve (102657).
• Nitrate tolerance. Intravenous N-acetyl cysteine seems to reduce the development of nitrate tolerance. Oral N-acetyl cysteine has shown mixed results for this use. Details: Some clinical research shows that concurrent intravenous or oral administration of N-acetyl cysteine reduces the development of nitroglycerin tolerance (832,2245,64546). However, other research suggests that oral N-acetyl cysteine does not reduce the development of nitroglycerin tolerance in patients with angina (2281,2282).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral N-acetyl cysteine is beneficial in patients with NASH. Details: One small clinical study in patients with NASH shows that taking N-acetyl cysteine 1.2 grams with metformin 850-1500 mg daily for 48 weeks reduces NASH activity scores and measures of steatosis and hepatocellular ballooning, but not inflammation or fibrosis, when compared to baseline. However, taking the same dose of N-acetyl cysteine and metformin along with ursodeoxycholic acid 15 mg/kg daily does not improve these outcomes, or improve liver enzyme levels, when compared with baseline (102026). The reasons for these disparate findings are unclear. Inadequate statistical power and the lack of a comparator group limit the validity of these findings.
• Obsessive-compulsive disorder (OCD). Oral N-acetyl cysteine might improve some symptoms of OCD when used with fluvoxamine in adults. Its effects when used in combination with other psychiatric medications or as monotherapy in children and adults is unclear. Details: Preliminary clinical research in adults shows that taking N-acetyl cysteine 1000 mg twice daily along with fluvoxamine 200 mg daily for 10 weeks modestly reduces overall symptoms of OCD and symptoms of obsession when compared with fluvoxamine alone. However, the addition of N-acetyl cysteine is not associated with an improvement in symptoms of compulsion, nor with a statistically significant increase in partial or complete responders, when compared with fluvoxamine alone (97048). A clinical trial in adults with OCD who are taking various psychiatric medications shows that adding oral N-acetyl cysteine 2000-4000 mg daily for 20 weeks does not reduce symptoms of OCD, or improve secondary outcomes such as anxiety, mood, functioning, or quality of life, when compared with placebo (108450). Over half (63%) of patients had a comorbid psychiatric diagnosis, limiting the applicability of these findings. Other preliminary clinical research in adults with moderate to severe OCD who are taking various psychiatric medications shows that taking N-acetyl cysteine 3000 mg daily for 16 weeks does not improve OCD symptoms when compared with placebo (97045). A very small preliminary clinical trial in children aged 8-17 years, most of whom are not taking psychiatric medications, shows some benefit for symptom reduction when N-acetyl cysteine 2700 mg daily for 12 weeks is compared with placebo (102656).
• Otitis media. Although there has been interest in using ear drops containing N-acetyl cysteine for otitis media, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Polycystic ovary syndrome (PCOS). Oral N-acetyl cysteine might improve pregnancy-related outcomes in PCOS, although it appears to be less effective than metformin. Evidence on its benefits for other symptoms of PCOS is conflicting. Details: Some research in patients with PCOS shows that N-acetyl cysteine can increase insulin sensitivity, improve hirsutism, and improve menstrual irregularity (64435,64550,91245,102121). It may also improve fasting insulin levels, but results are conflicting (64435,64550,91245). Other research shows that N-acetyl cysteine, alone or as a specific combination product (Ovaric HP, Just Pharma), increases ovulation rates in some, but not all, patients with PCOS (64480,64550,64553,91246,91247,102121). A meta-analysis of clinical research suggests that N-acetyl cysteine increases the odds of having a live birth, getting pregnant, and/or ovulating by about 3-fold when compared with placebo. Its effects on the odds of pregnancy and ovulation appear to be greater in those resistant to clomiphene citrate. However, when compared with metformin, N-acetyl cysteine appears to decrease the odds of getting pregnant by about 60% and decrease the odds of ovulation by about 87%. N-acetyl cysteine also does not appear to reduce the rate of miscarriage, menstrual irregularity, or the severity of acne or hirsutism in people with PCOS (93057). Another meta-analysis shows that N-acetyl cysteine in various doses is associated with an insignificant improvement in ovulation and pregnancy rate, multiple pregnancy rate, and miscarriage rate, and is less efficacious than metformin for all of these outcomes (106888).
• Post-traumatic stress disorder (PTSD). It is unclear if oral N-acetyl cysteine is beneficial in veterans with PTSD. Details: A small clinical study in veterans with PTSD and a history of substance use disorders shows that taking N-acetyl cysteine 1200 mg orally twice daily for 8 weeks while receiving cognitive behavioral therapy reduces depressive symptoms and the rate of self-reported PTSD symptoms when compared with cognitive behavioral therapy plus placebo. Additionally, receiving N-acetyl cysteine reduces the amount and frequency of cravings by 81% and 72%, respectively, compared to a reduction of 32% and 29% for those receiving cognitive behavioral therapy with placebo. The use of N-acetyl cysteine did not impact the intensity of cravings or the actual rate of substance use during the study, which was low for all patients (97037).
• Postmenopausal conditions. It is unclear if oral N-acetyl cysteine is beneficial for preventing postmenopausal bone loss. Details: One small clinical trial shows that taking N-acetyl cysteine 2 grams daily for 3 months does not reduce postmenopausal bone loss when compared with placebo (64576).
• Preterm labor. It is unclear if oral N-acetyl cysteine is beneficial for reducing the risk for preterm labor. Details: Some clinical research shows that taking N-acetyl cysteine 0.6 grams daily orally in combination with 17-hydroxyprogesterone caproate (17-OHPC), beginning at 16 to 18 weeks gestation and continuing until active labor, increases the likelihood of reaching 36 weeks gestation and increases gestational age at delivery in adults with previous preterm labor and bacterial vaginosis when compared with 17-OHPC alone (64615). However, taking oral N-acetyl cysteine 0.6 grams every 8 hours, beginning at 25 to 33 weeks gestation and continuing until delivery, does not improve the treatment-to-delivery interval when compared with placebo in adults with early onset severe pre-eclampsia and/or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome (64493).
• Radiation-induced sialadenitis. It is unclear if mouthwash containing N-acetyl cysteine is beneficial for reducing dry mouth during chemoradiotherapy. Details: One clinical trial in a small group of patients undergoing chemoradiotherapy for head and neck cancer shows that using a mouth rinse containing N-acetyl cysteine 500 mg five times daily during radiotherapy and 2 weeks postradiotherapy improves daytime and total sticky saliva and feelings of dry mouth by up to 38% when compared with placebo. However, N-acetyl cysteine does not seem to improve nighttime symptoms (102661).
• Schizophrenia. Oral N-acetyl cysteine seems to improve negative symptoms of schizophrenia. The benefits of N-acetyl cysteine on positive symptoms of schizophrenia are less clear. Details: A meta-analysis of clinical research shows that taking N-acetyl cysteine for at least 6 months has a small to moderate effect on negative symptoms when compared with placebo. However, taking N-acetyl cysteine for only 8 weeks does not reduce negative symptoms, suggesting that a longer duration of treatment may be necessary (102658). Individual clinical studies show that N-acetyl cysteine does not improve positive symptoms, social function, cognition, and clinical global impression when compared with placebo (64605,99528). However, a meta-analysis of available research shows that taking N-acetyl cysteine for any duration has a small effect on positive symptoms, a moderate effect on working memory, and a large effect on overall symptoms (102658). It is possible that many individual studies were underpowered to detect a difference.
• Sepsis. Small clinical studies suggest that intravenous N-acetyl cysteine may improve respiratory function and tissue oxygenation, but not mortality, in patients with septic shock. Details: Two small clinical studies show that intravenous N-acetyl cysteine might improve respiratory function and tissue oxygenation, but not mortality, in some patients with recently diagnosed septic shock when compared with placebo (64760,64797).
• Sjogren syndrome. Small clinical studies suggest that oral N-acetyl cysteine may improve ocular and oral manifestations of this condition. Details: Two small clinical studies in adults with Sjogren syndrome show that taking oral N-acetyl cysteine 200 mg three times daily for 4 weeks reduces eye soreness and irritability, bad breath, and daytime thirst when compared with a control group; however, objective signs of dry eye were not improved (64673,64812).
• Systemic lupus erythematosus (SLE). It is unclear if oral N-acetyl cysteine is beneficial in patients with SLE. Details: One small clinical trial shows that taking N-acetyl cysteine orally 2.4-4.8 grams daily for 3 months significantly reduces disease activity and fatigue when compared with placebo in patients with SLE (91242).
• Thrombocytopenia. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A very small clinical study in adults with primary immune thrombocytopenia resistant or refractory to steroid therapy shows taking N-acetyl cysteine 400 mg every 8 hours with atorvastatin daily for at least one month at least doubles platelet count or increases it above 30 × 109/L compared to baseline in 60% of participants. However, 40% of participants did not respond to treatment (111572). It is unclear if this effect is due to N-acetyl cysteine, atorvastatin, or the combination. The validity of these findings is limited by the very small sample size, insufficient randomization, lack of a comparator group, and low retention rate, especially in the non-responder group.
• Tourette syndrome. It is unclear if oral N-acetyl cysteine is beneficial in patients with this condition. Details: One small clinical trial in children 8-17 years of age with Tourette syndrome shows that taking N-acetyl cysteine 600 mg twice daily for 2 weeks, followed by 1200 mg twice daily for the next 10 weeks, does not improve tic symptoms, premonitory urges, or the comorbid symptoms of obsessive-compulsive disorder (OCD), attention deficit-hyperactivity disorder (ADHD), anxiety, or depression when compared with placebo (97040).
• Trichotillomania. Oral N-acetyl cysteine might offer some benefit to adults, but not children, with trichotillomania. Details: One small clinical trial in adults shows that taking N-acetyl cysteine orally, in doses up to 2400 mg daily, significantly decreases the urge to pull hair, the amount of hair pulled, and patients' perception of their control over hair pulling as measured by a self-rating scale. After 12 weeks of treatment, scores decreased by 40% (16840). However, in children, taking N-acetyl cysteine in doses up to 2400 mg daily for 12 weeks does not seem to improve hair pulling when compared with placebo (91235).
• Ulcerative colitis. It is unclear if oral N-acetyl cysteine is beneficial in patients with ulcerative colitis. Details: One small clinical trial shows that oral N-acetyl cysteine 0.8 grams daily in combination with mesalamine 2.4 grams daily for 4 weeks does not improve the rate of clinical remission in individuals with ulcerative colitis when compared with mesalamine alone (64606).
• Urinary tract infections (UTIs). Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in female breast cancer survivors has found that taking the combination of D-mannose 500 mg, N-acetyl cysteine 100 mg, and Morinda citrifolia fruit extract 200 mg daily for 2 months in addition to antibiotic therapy is associated with reduced recurrence of UTIs and urinary discomfort when compared with antibiotics alone (97360).
• Uterine fibroids. It is unclear if oral N-acetyl cysteine is beneficial in patients with uterine fibroids. Details: Preliminary clinical research shows that taking N-acetyl cysteine 600 mg daily for 12 weeks reduces the volume of uterine fibroids by about 25%, compared with a reduction of about 1% with placebo. N-acetyl cysteine also reduces painful and heavy menstrual bleeding when compared with placebo (106889).
• Wound healing. It is unclear if postoperative intravenous N-acetyl cysteine is beneficial in patients undergoing lower extremity amputation. Details: A clinical study in patients undergoing lower extremity amputation due to critical limb-threatening ischemia shows that receiving postoperative intravenous N-acetyl cysteine 1200 mg twice daily for 5 days, beginning within 3 hours after surgery, improves tissue perfusion from days 3 to 5 and amputation stump healing at day 30 in patients that are defined as high-risk, but not in the intent-to-treat population, when compared with placebo (108448). The validity of these findings is limited due to the short duration of treatment and the inclusion of both above-the-knee and below-the-knee amputations. More evidence is needed to rate N-acetyl cysteine for these uses.

(Read more about N-ACETYL CYSTEINE (NAC))

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Nonmelanoma skin cancer. Oral niacinamide might reduce the rate of nonmelanoma skin cancer development. Details: One clinical study in patients with a history of nonmelanoma skin cancers shows that taking niacinamide 500 mg orally twice daily for 12 months reduces the rate of new nonmelanoma skin cancers at 12 months by 23% and the number of actinic keratoses by 13% when compared with placebo (93362). Other clinical research shows that taking niacinamide (Nature's Own, Virginia) 500 mg orally once or twice daily for 4 months reduces the total number of actinic keratoses by up to 35% and decreases the odds of developing at least one nonmelanoma skin cancer by 86% when compared with placebo in patients with at least four actinic keratoses (93365). However, some conflicting research exists. One small clinical study in adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days does not reduce the number of actinic keratoses when compared with control. However, the validity of this study is limited by the short study duration (107714). A meta-analysis of many small clinical trials shows that using niacinamide, up to 2000 mg orally or 4% topically, daily for 1 month to 5 years lowers the risk of skin cancer, including basal cell carcinoma and cutaneous squamous cell carcinoma by 50% when compared with control. Using niacinamide did not reduce the risk of actinic keratoses. However, the validity of this study is limited by inclusion of populations with different cancer risks and high heterogeneity (110497).
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560).
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was administered intravenously, containing niacinamide 20 mg, inosine 40 mg, riboflavin 4 mg, and succinate 200 mg, for 10 days followed by orally, containing niacinamide 50 mg, inosine 100 mg, riboflavin 10 mg and succinate 600 mg, for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves uneven skin pigmentation. Details: A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

EFFECTIVE

• Pantothenic acid deficiency. Taking pantothenic acid 5-10 mg daily is effective for treating and preventing pantothenic acid deficiency (15).

POSSIBLY INEFFECTIVE

• Radiation dermatitis. Topical dexpanthenol does not seem to be beneficial for preventing or treating radiation dermatitis. Details: Applying dexpanthenol, an analog of pantothenic acid, twice daily to areas of irradiated skin does not seem to reduce erythema, desquamation, itching, or pain following radiation treatment (7192). Also, applying dexpanthenol 0.5% cream (Bepanthen, Hoffmann LaRoche ) daily during radiation therapy and for 2 weeks after completing radiation therapy is less effective than methylprednisolone aceponate 0.1% cream (Advantan) at reducing radiation-induced skin irritation (67779).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral or topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In adults with mild to moderate acne, clinical research shows that taking a specific supplement (Pantothen, Avilan Marketing LLC) providing pantothenic acid 1.1 grams twice daily in addition to other B vitamins for 12 weeks modestly reduces total and non-inflammatory lesion counts when compared with placebo (105188). Also, in adolescents or young adults with mild to moderate acne, preliminary clinical research shows that topical application with a gel containing D-panthenol 4%, hydrogen peroxide 4%, and salicylic acid 0.5% once daily for 60 days modestly reduces acne lesions when compared with baseline (105189). The validity of this finding is limited by the lack of a comparator group.
• Alcoholism. Although there is interest in using oral pantothenic acid for improving recovery from alcoholism, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral pantothenic acid for allergic rhinitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Alopecia areata. Pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with diffuse hair loss shows that intramuscular administration of dexpanthenol 250 mg and biotin 5 mg once weekly for 6 weeks reduces hair fall count at weeks 1 and 8, but only increases hair density at week 1, when compared to baseline (111366). The validity of these findings is limited by the study's small size, short duration, and lack of comparator group.
• Anxiety. Although there is interest in using oral pantothenic acid for anxiety, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Asthma. Although there is interest in using oral pantothenic acid for asthma, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Athletic performance. Although there is interest in using oral pantothenic acid to improve athletic performance, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Oral pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some small outdated clinical studies in children diagnosed with hyperkinesis suggest that taking calcium pantothenate 1.2 grams, alone or in combination with niacinamide, ascorbic acid, and pyridoxine, does not improve symptoms of hyperactivity when compared with placebo (3351,9957). It is unclear what effects pantothenic may have, if any, in children with a modern diagnosis of ADHD.
• Atopic dermatitis (eczema). It is unclear if topical pantothenic acid is beneficial in infants or children with atopic dermatitis. Details: One preliminary clinical trial in infants and children with stable mild atopic dermatitis shows that topical application of an emollient containing panthenol (Bepanthen, SensiDaily, Bayer Consumer Care AG) for 3 months is as effective as a reference emollient for reducing symptoms and preventing a flare. However, the efficacy of the reference emollient (Stelatopia Emollient Cream, Mustela; Laboratoires Expanscience) is unclear based on available preliminary clinical research (105190).
• Autism spectrum disorder. Although there is interest in using oral pantothenic acid for autism spectrum disorder, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Carpal tunnel syndrome. Although there is interest in using oral pantothenic acid for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral pantothenic acid for CFS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Conjunctivitis. Although there is interest in using oral or ocular pantothenic acid for conjunctivitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Constipation. It is unclear if oral or intramuscular dexpanthenol is beneficial for constipation. Details: Preliminary clinical research shows that administering dexpanthenol (Bepanthene), an analog of pantothenic acid, 400 mg orally or 500 mg intramuscularly daily for 5 days decreases the time to a bowel movement in patients with chronic or occasional constipation when compared with an oral placebo (67822).
• Dandruff. Although there is interest in using oral or topical pantothenic acid for dandruff, is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Depression. Although there is interest in using oral pantothenic acid for depression, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Diaper rash. Although there is interest in using topical pantothenic acid for diaper rash, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry eye. Although there is interest in using ocular pantothenic acid for dry eye, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry skin. It is unclear if topical dexpanthenol is beneficial for patients with dry skin. Details: A small, open-label study in healthy adults with dry skin shows that cleansing the skin with a dexpanthenol-containing liquid cleanser (DCLC, Bepanthen SensiControl Daily Gentle Body Wash) daily for 4 weeks increases stratum corneum hydration by 17% without affecting skin barrier function, pH, or microbiome when compared to baseline (111262). The validity of these findings is limited by the lack of blinding and a comparator group.
• Epilepsy. Although there is interest in using oral pantothenic acid for epilepsy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Eye trauma. It is unclear if ocular dexpanthenol is beneficial for eye trauma. Details: Some preliminary clinical research shows that using eyedrops containing dexpanthenol 5%, a derivative of pantothenic acid, two drops four times daily for 28 days following surgery for retinal detachment reduces eye pain and discomfort when compared with placebo drops (67783). However, using a specific dexpanthenol 5% ointment (Bepanthen) does not seem to improve corneal epithelial wound healing following phototherapeutic keratectomy when compared with placebo (67801).
• Heart failure. Although there is interest in using oral pantothenic acid for heart failure, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Herpes zoster (shingles). Although there is interest in using oral or topical pantothenic acid for shingles, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Insomnia. Although there is interest in using oral pantothenic acid for insomnia, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Laser skin resurfacing. It is unclear if topical dexpanthenol or pantothenic acid can reduce adverse effects after laser skin resurfacing procedures. Details: A preliminary clinical study shows that use of a dexpanthenol-containing ointment (Bepanthen Wound Healing Ointment, Bayer) once daily modestly reduces the diameter of lesions up to 3 days after fractional carbon dioxide laser resurfacing when compared with petroleum jelly (105743). Also, applying a specific cream (Cicaplast Baume B5 cream, L'Oreal) containing panthenol 5%, madecassoside, copper, zinc, and manganese to one side of the face for 28 days reduces decrustation time by approximately one day when compared with a control emollient. Redness and swelling were lower at 3 days, but there was no difference in pain and burning (105742). It is unclear if these effects are due to pantothenic acid, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral pantothenic acid for MS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Muscular dystrophy. Although there is interest in using oral pantothenic acid for muscular dystrophy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Nipple fissures. Although there is interest in using topical pantothenic acid for nipple fissures, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Obesity. Although there is interest in using oral pantothenic acid for obesity, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Pain (chronic). It is unclear if oral or topical pantothenic acid is beneficial for the management of various forms of chronic pain. Details: Although there is interest in using oral or topical pantothenic acid for various forms of chronic pain, including neuropathy and arthritis, there is limited information available about the clinical effects of pantothenic acid for this purpose. One review of preliminary clinical research found that calcium pantothenate does not reduce symptoms of arthritis in patients with rheumatoid arthritis or osteoarthritis (10433).
• Parkinson disease. Although there is interest in using oral pantothenic acid for Parkinson disease, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical pantothenic acid for poison ivy dermatitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Postoperative pain. It is unclear if oral pantothenic acid is beneficial for postoperative pain. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily reduces pain when compared with placebo. Postoperative pain was modestly reduced at 1, 3, 7, and 14 days after surgery (105191).
• Postoperative sore throat. It is unclear if pantothenic acid lozenges are beneficial for postoperative sore throat. Details: Preliminary clinical research shows that taking two lozenges containing dexpanthenol, an analog of pantothenic acid, 200 mg 30 minutes prior to general anesthesia reduces the incidence and severity of postoperative sore throat when compared with a benzydamine hydrochloride or placebo spray (67792).
• Pregnancy-related leg cramps. Although there is interest in using oral pantothenic acid for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral pantothenic acid for PMS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Respiratory tract infections. Although there is interest in using oral pantothenic acid for respiratory tract infections, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Rhinosinusitis. It is unclear if nasal dexpanthenol is beneficial for rhinosinusitis. Details: Preliminary clinical research shows that using a nasal spray (MarPlus) containing dexpanthenol, an analog of pantothenic acid, on the first, second, fourth, and sixth week after endoscopic sinus surgery reduces nasal discharge, but not other symptoms associated with chronic rhinosinusitis, when compared with saline nasal spray (67808).
• Skin irritation. It is unclear if topical dexpanthenol is beneficial for preventing or treating skin irritation due to sodium lauryl sulfate. Details: Preliminary clinical research shows that applying dexpanthenol (Bepanthol Handbalsam), an analog of pantothenic acid, twice daily for 26 days does not prevent sodium lauryl sulfate-induced skin irritation (67785). However, dexpanthenol may be effective for treating skin irritation caused by sodium lauryl sulfate. Use of an ointment containing dexpanthenol 1% to 5% twice daily for up to 30 days following skin exposure to sodium lauryl sulfate seems to reduce skin water loss, skin roughness, and skin inflammation when compared to control (67802,67806).
• Ulcerative colitis. Although there is interest in using oral or rectal pantothenic acid for ulcerative colitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Vertigo. Although there is interest in using oral pantothenic acid for vertigo, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Wound healing. Preliminary clinical research suggests that oral dexpanthenol might be beneficial for wound healing. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily improves wound healing when compared with placebo. Depending on the type of surgery, wound healing occurred in 2.3-2.9 times as many patients within 7 days of surgery, and in 13% to 35% more patients within 14 days, when compared with placebo (105191). More evidence is needed to rate pantothenic acid for these uses.

(Read more about PANTOTHENIC ACID)

EFFECTIVE

• Sunburn. PABA is an FDA-approved sunscreen (266,8952). PABA seems to be effective during sweating, but not when skin is immersed in water (272).

POSSIBLY EFFECTIVE

• Peyronie disease. PABA is FDA-approved for use in this condition. Clinical research shows that taking the specific PABA product (POTABA, Glenwood LLC.) can reduce penile curvature and deterioration (1067,8951,67982,68031).

POSSIBLY INEFFECTIVE

• Scleroderma. Although PABA is FDA-approved for scleroderma, as well as morphea, a localized form of scleroderma, evidence supporting its use is limited. Some retrospective studies suggest it might help for some symptoms of scleroderma, but the most convincing evidence shows that it is not beneficial (1071,1073,1074,1075).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Herpes keratitis. Preliminary clinical research shows that, in most patients, using a specific PABA 0.007% ophthalmic solution (Actipol), given as eye drops with or without concomitant local injections, can be effective in treating herpes keratitis, a type of corneal eye infection caused by herpes simplex virus. Clinical research suggests this PABA solution is as effective or more effective than acyclovir and more effective than idoxuridine (67957,67963).
• Inflammatory myopathies. PABA is FDA-approved for use in dermatomyositis, a type of inflammatory myopathy, but there is limited evidence to support this use (10).
• Pemphigus. PABA is FDA-approved for use in pemphigus, but there is limited evidence to support this use (10). More evidence is needed to rate PABA for these uses.

(Read more about PARA-AMINOBENZOIC ACID (PABA))

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg/day. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not appear to reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo . This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan has found that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

LIKELY EFFECTIVE

• Selenium deficiency. Oral selenium is effective for the treatment and prevention of selenium deficiency. Details: Selenium supplementation is effective for reversing symptoms of selenium deficiency, as well as for preventing the development of selenium deficiency (4844,90357).

POSSIBLY EFFECTIVE

• Autoimmune thyroiditis. Oral selenium seems to improve autoimmune thyroiditis in adults but not in children. Details: Clinical research in adults with thyroiditis shows that taking selenium up to 200 mcg daily in combination with levothyroxine reduces thyroid peroxidase antibodies by about 6% to 30% more than placebo after 3-12 months of treatment (9797,17510,17511,17512,17513,17515,17516,97943,104424). Selenium also seems to improve measures of quality of life such as feelings of well-being and mood (17515). Doses under 200 mcg daily might not be as effective (17512); selenomethionine might be more effective than sodium selenite (97943). Some research shows that selenium might be more effective in patients with more severe disease activity and less effective in patients with only moderate disease activity (9797,17513,17515). Also, selenium might not reduce thyroid autoantibodies in patients newly diagnosed with thyroiditis not receiving concurrent levothyroxine (97943). There is no reliable evidence about the effect of selenium on thyroid function or thyroid morphology. Despite positive findings in adults, clinical research in children suggests that taking selenium 50-200 mcg daily for 3-12 months does not significantly improve thyroid peroxidase antibodies, thyroglobulin antibody, or thyroid echogenicity (17514,90362).
• Kashin-Beck disease. Selenium seems to help prevent Kashin-Beck disease, but does not improve symptoms in patients with existing disease. Details: A meta-analysis of prospective studies conducted in China shows that adding salt enriched with selenium to the diet of healthy children for up to 4 years reduces the odds of developing Kashin-Beck disease by 84% when compared with the use of iodine salt. Additionally, in children with Kashin-Beck disease, adding salt enriched with selenium to the diet might help heal metaphyseal lesions (97945). However, selenium does not seem to improve symptoms in those with existing disease. A clinical trial in children with Kashin-Beck disease shows that selenium supplementation does not improve joint pain or mobility when compared with placebo (55941).
• Pre-eclampsia. Oral selenium might reduce the risk of pre-eclampsia in pregnant patients. Details: A meta-analysis of three low-quality clinical trials in pregnant patients shows that taking selenium 60-100 mcg daily for up to 6 months reduces the risk of pre-eclampsia by 72% when compared with placebo. Additionally, a meta-analysis of population research has found that the risk of pre-eclampsia is higher in pregnant patients with low selenium levels. Selenium levels were about 6.5 mcg/L lower in those who developed pre-eclampsia compared with those who did not (97946).

POSSIBLY INEFFECTIVE

• Asthma. Oral selenium does not seem to improve asthma symptoms. Details: Epidemiological research has found that plasma selenium concentration is not associated with asthma (74422). Also, clinical research in patients with asthma shows that taking selenium 100 mcg daily for 14-24 weeks does not improve symptoms, lung function, use of rescue inhalers, or quality of life when compared with placebo (74490,74387).
• Atopic dermatitis (eczema). Oral selenium-enriched yeast does not seem to improve eczema symptoms. Details: A small clinical study in patients with eczema shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not improve symptom severity when compared with placebo (74456).
• Bladder cancer. Despite promising initial research, oral selenium does not seem to prevent bladder cancer development or recurrence. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and bladder cancer risk based on two small studies. However, the FDA determined that it is highly uncertain that selenium supplements reduce the risk of bladder cancer (102373). Since that time, the available research has not confirmed an association between selenium and bladder cancer risk. Epidemiological research has found that selenium supplementation is not associated with a reduced risk of bladder cancer (97085). Furthermore, a clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for about 7 years does not prevent bladder cancer in older men (90352). Selenium also does not seem to prevent bladder cancer recurrence. A clinical study shows that taking selenium yeast 200 mcg daily for 3 years does not prevent the recurrence of bladder cancer when compared with placebo in patients that had undergone a transurethral resection for non-invasive bladder cancer (97087).
• Cardiovascular disease (CVD). Most research shows that oral selenium does not reduce the risk of CVD. Details: Meta-analyses of clinical trials in patients with and without risk factors for CVD show that taking selenium alone or with other supplements for up to 8 years does not reduce the risk of CVD mortality or fatal and non-fatal CVD events (90360,97078). When reported, patients in these studies all had adequate plasma selenium levels at baseline (90360).
• Colorectal cancer. Oral selenium does not seem to prevent cancer of the colon and rectum. Details: Epidemiological research has found no association between serum concentrations of selenium and the risk of developing colorectal cancer (74321,97085). Also, meta-analyses of clinical research, as well as individual clinical trials, show that taking selenium 100-200 mcg daily, alone or in combination with other vitamins and minerals, does not reduce the risk of colorectal cancer when compared with control (16707,34676,90361,97092).
• Diabetes. Increased intake of selenium, either in the diet or as a supplement, is associated with an increased risk for developing type 2 diabetes. It is unclear if oral selenium is beneficial in patients with type 2 diabetes. Details: Observational research has found that high serum selenium levels, high dietary selenium intake, and selenium supplementation are each linked to an increased risk of developing diabetes (97091,99661). Consuming more than the recommended dietary allowance (RDA) of selenium daily is associated with an increased risk of developing diabetes when compared with consuming less than the RDA (99661). However, the effect of short-term selenium supplementation in patients with diabetes is unclear. Three small clinical trials in patients with type 2 diabetes and various other conditions, such as cardiovascular disease or kidney failure, show that taking selenium (Nature Made) 200 mcg daily for 8-24 weeks does not improve fasting blood glucose. However, taking selenium seems to reduce insulin resistance and improve insulin sensitivity and levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol when compared with placebo (97084,97086,109092). These three studies were included in a meta-analysis of 10 small, mostly moderate-quality clinical studies. This analysis shows that taking selenium 100-200 mcg daily for 4 to 24 weeks improves markers of insulin resistance and reduces serum insulin levels but does not lower fasting blood glucose when compared with placebo. Selenium supplementation did not reduce total or LDL cholesterol or triglycerides but may improve HDL cholesterol (110593). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with diabetes, gestational diabetes, cardiovascular disease, heart failure, or obesity. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
• Dyslipidemia. Most research shows that oral selenium supplementation does not improve cholesterol levels. Details: A meta-analysis of 11 clinical studies in adults with dyslipidemia shows that taking selenium 50-300 mcg daily for 8-24 weeks does not increase high-density lipoprotein (HDL) cholesterol levels or decrease total or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. Taking selenium might modestly improve triglyceride levels, but this improvement is unlikely to be considered clinically significant (99662). Another meta-analysis of 21 mostly small, low-quality clinical studies, some of which were included in the prior meta-analysis, shows that taking various forms of selenium may modestly decrease total cholesterol levels, but does not improve triglycerides, LDL, or HDL cholesterol when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which assessed various selenium dosing regimens and enrolled healthy patients or those with various cardiovascular and non-cardiovascular conditions.
• Low birth weight. Oral or intravenous selenium supplementation does not improve outcomes in low birth weight infants. Details: Low selenium levels have been documented in low birth weight infants. However, selenium supplementation, orally or intravenously, does not appear to improve most outcomes in low birth weight infants. Clinical research shows that administering selenium, either as 7-10 mcg/kg daily parenterally or 5 mcg/kg daily orally, does not improve oxygen dependency or reduce the risk of death in low birth weight infants when compared with placebo. However, supplementation decreases the incidence of sepsis by up to 33% (74288,97083).
• Lung cancer. Oral selenium does not reduce lung cancer risk in most patients. Details: A meta-analysis of three large clinical trials of over 20,000 patients, including patients with resected stage I non-small-cell lung cancer, shows that taking selenium 200-400 mcg daily for up to 5 years does not reduce the risk of lung cancer when compared with control (92912,97092). A secondary analysis of one of these studies found that selenium supplementation might reduce lung cancer risk in people with selenium levels below 105 ng/mL (9798). Also, a large study in healthy Chinese patients shows no benefit of using selenium in combination with other nutrients for over 5 years when compared with control (34539).
• Nonmelanoma skin cancer. Oral selenium does not reduce the risk of nonmelanoma skin cancer and has been linked to increased risk in some patients. Details: Epidemiological research has found that higher selenium intake is not associated with a reduced risk of nonmelanoma skin cancer (97085). Furthermore, clinical research shows that taking selenium orally 200 mcg daily does not reduce the risk of basal cell carcinoma when compared with control (2664,10687). In addition, some evidence shows that daily selenium supplementation might increase the risk of squamous cell carcinoma and total non-melanoma skin cancer (10687).
• Prostate cancer. Oral selenium does not seem to reduce prostate cancer risk. Details: Population studies have found that higher serum or toenail selenium levels are associated with a decreased risk of prostate cancer (8734,8735,8736,92911,10263). However, clinical research does not support this finding. A meta-analysis of 5 large clinical trials of over 20,000 patients shows that selenium 200-400 mcg daily for up to 5 years does not reduce the risk of prostate cancer when compared with control (97092). A 7-14 year follow-up study of one of these trials shows there was still no reduction of prostate cancer risk (17688). Selenium has also shown no benefit when used in combination with other supplements. In a large-scale clinical study (SU.VI.MAX), taking selenium 100 mcg in combination with vitamin C, vitamin E, beta-carotene, and zinc did not reduce prostate cancer risk (14135). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and prostate cancer risk, stating that it is highly unlikely that selenium supplements reduce the risk of prostate cancer (102373).
• Psoriasis. Oral selenium does not seem to reduce psoriasis severity. Details: Clinical research shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not reduce the severity of psoriasis when compared with placebo (74460).
• Sepsis. Intravenous selenium does not appear to improve outcomes in septic adults. Details: Earlier meta-analyses of clinical trials in septic adults showed that parenteral administration of selenium, along with routine nutritional interventions, reduces the risk of mortality by 11% to 27% when compared with placebo (90347,92907,92910). However, a more recent meta-analysis, which includes a large, multi-center study of over 1000 cases, shows that parenteral selenium does not reduce mortality in septic adults at 28, 90, or 180 days when compared with placebo (99658). Enteral selenium with other nutrients has been studied for sepsis in children. Clinical research in children shows that taking enteral selenium 40-400 mcg daily with zinc, glutamine, and IV metoclopramide is no more effective than whey protein for reducing time to first episode of nosocomial infection or sepsis in the intensive care unit (ICU). However, the selenium combination treatment might reduce the risk for sepsis in immunocompromised pediatric patients (86095).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral selenium reduces the risk of cognitive decline in older adults. Details: A cross-sectional study in elderly Americans has found that lower blood levels of selenium are associated with a greater risk of poor cognitive scores when compared with higher levels (104426).
• Alcohol-related liver disease. Although there is interest in using oral selenium for alcohol-related liver disease, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral selenium for allergic rhinitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Arsenic poisoning. It is unclear if oral selenized yeast is beneficial for patients that were exposed to high levels of arsenic in the environment. Details: A small clinical study in Chinese people environmentally exposed to high concentrations of arsenic shows that taking selenized yeast providing 100-200 mcg of selenium daily for 14 months decreases the concentration of arsenic and symptoms of toxicity when compared with placebo (7831).
• Benign prostatic hyperplasia (BPH). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in men with BPH shows that taking selenium 240 mcg plus silymarin 570 mg daily for 6 months reduces lower urinary tract symptoms when compared with placebo (88155). Another clinical study in men with BPH shows that taking tamsulosin 0.4 mg plus a specific product containing selenium, saw palmetto, and lycopene (Profluss, Ayanda AS) daily for one year improves lower urinary tract symptoms and urodynamic parameters when compared with tamsulosin-alone (90354). It is unclear if these effects are due to selenium, other ingredients, or the combinations.
• Burns. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with burns on 46% of their body surface suggest that taking a combination of copper 2.5-3.1 mg, selenium 315-380 mcg, and zinc 26.2-31.4 mg daily reduces the incidence of hospital-acquired pneumonia, but does not seem to improve wound healing, hospital stay, or mortality, when compared with placebo (6520,74382). Another very small clinical study in burn patients suggests that taking copper 4.5 mg, selenium 190 mcg, and zinc 40 mg daily reduces the duration of hospitalization, but does not have an effect on recovery and wound treatment requirements, when compared with standard dietary doses of these nutrients (74485).
• Cancer. Selenium does not seem to reduce the risk of cancer in most people, but it might be beneficial in those with low selenium levels and in men. Details: Meta-analyses of clinical research and several clinical studies show that selenium supplementation does not reduce the incidence of cancer or cancer-related mortality when compared with control (14109,34538,74414,97078,97092). In clinical studies, selenium 100-400 mcg taken daily for 2-7.5 years with or without additional antioxidants did not reduce overall cancer risk (14109,34538,74414). However, most evidence did not assess baseline selenium levels. Other evidence suggests that selenium may have a benefit in men and in people with lower selenium levels. Epidemiological research has found that selenium intake at the recommended daily allowance (RDA) of 55 mcg or higher is associated with decreased cancer incidence and cancer mortality, especially in men (97085,103164). However, this research suggests that cancer risk was also influenced by age, body mass index, and smoking status (103164). Some clinical research also suggests that taking selenium might decrease the risk of cancer, when only men are considered (14109). An older meta-analysis of clinical research suggests that selenium was particularly beneficial in patients with lower baseline levels of selenium and in patients at high risk for cancer (90350). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim stating that consumption of selenium may produce anticarcinogenic effects and reduce the risk for certain forms of cancer. However, the FDA has determined that the evidence is limited and inconclusive (102374).
• Cataracts. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An ancillary clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for around 5.6 years does not reduce the risk of age-related cataracts in men when compared with placebo (92902).
• Cervical dysplasia. It is unclear if oral selenized yeast is beneficial for patients with cervical dysplasia of mild severity. Details: A small clinical study in patients with cervical intraepithelial neoplasia grade 1 (CIN1) shows that taking yeast containing selenium 200 mcg daily for 6 months resulted in regression of CIN1 in 88% of participants, compared with regression in only 55% of participants taking placebo (97944).
• Chemotherapy-induced nephrotoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-induced nephrotoxicity when compared with a placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral selenium for CFS, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Cirrhosis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with primary biliary cirrhosis shows that taking a combination of selenium, vitamin A, vitamin C, vitamin E, methionine, and coenzyme Q10 for 12 weeks does not improve fatigue or any other disease-related symptoms when compared with placebo (34494).
• Cisplatin-associated ototoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-associated hearing loss when compared with placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Colorectal adenoma. It is unclear if oral selenium prevents recurrence of adenomas in the colon and rectum. Details: A large clinical study in patients with a history of colorectal adenomas shows that taking a specific selenium supplement (SelenoExcell High Selenium Yeast, Cypress Systems) 200 mcg daily for about 33 months does not reduce adenoma recurrence when compared with placebo. However, in a sub-group of patients with advanced adenomas at baseline, selenium seems to reduce risk of recurrence by 18% when compared with placebo (97091). Some research also shows that taking selenium in combination with zinc, and vitamins A, C, and E reduces adenoma recurrence when compared with placebo (92903). It is not clear any benefit is due to selenium, other nutrients, or the combination.
• Congestive heart failure (CHF). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in elderly patients with heart failure living in Sweden shows that taking a specific selenium supplement (SelenoPrecise, Pharma Nord) 200 mcg plus a specific coenzyme Q10 supplement (Bio-Quinon, Pharma Nord) 200 mg daily for about 4 years reduces the risk of cardiovascular mortality by about 55% when compared with placebo (92904). The risk reduction seems to be most pronounced in patients with lower selenium levels (97906). Furthermore, at 10- and 12-year follow-ups, cardiovascular mortality in the treatment group continued to be 49% and 41% lower, respectively, when compared with placebo (96546,97466). It is unclear if the benefit can be attributed to selenium, coenzyme Q10, or the combination.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral selenized yeast is beneficial for patients undergoing CABG surgery. Details: A small clinical study in patients undergoing CABG surgery shows that taking selenium 200 mcg daily as selenium yeast for 4 weeks improves glycemic control, lipid levels, and markers of inflammation when compared with placebo (103163). It is not known whether this influences the outcome or complications of CABG surgery.
• Critical illness (trauma). Evidence on the use of intravenous selenium in critically ill patients is conflicting. Details: The most recent meta-analysis of 24 clinical trials in critically ill patients shows that intravenous selenium does not improve survival over 6 months, shorten hospital stay, or reduce intensive care unit (ICU) stay, infectious complications, development of acute kidney failure, or duration of mechanical ventilation when compared with control. Also, length of ICU stay was increased by about 4.5-fold in patients receiving selenium in doses of more than 1000 mcg daily (109086). These findings are similar to those of a meta-analysis of 21 randomized controlled trials in critically ill patients from 2016 which shows that intravenous selenium given alone or with other nutrients does not improve mortality, duration of hospital stay, or kidney function when compared with control (97090). However, another recent meta-analysis of 19 clinical trials in critically ill patients shows that intravenous selenium reduces total mortality by 14% and shortens hospital stay by about 2 days when compared with control, without affecting ICU stay, duration of mechanical ventilation, or mortality over 28 days (101345). The reasons for these discrepancies are not clear and do not seem to be completely explained by differences in doses or durations of selenium (109086). Some reasons for the discrepancies might include differing analytic methods used in meta-analyses, as well as variations in forms of selenium, concomitant treatments, and specific patient populations. One sub-analysis shows that, when limited to randomized controlled trials examining the effect of selenium supplementation in patients sustaining traumatic injury, the odds of mortality was reduced by about 26% and duration of ICU and hospital stay were modestly reduced. There was no effect on infectious complications (109090).
• Dementia. It is unclear if oral selenium prevents dementia or reduces symptoms. Details: Observational research has found that taking selenium 200 mcg daily for 4 years does not decrease the incidence of dementia in men 60 years or older (93570). However, the follow-up period may not have been long enough to reliably detect the effect of selenium on the development of dementia. Also, the screening method used to detect new cases of dementia may have failed to identify individuals presenting with only the initial symptomatic stages of the disease (93570,93571).
• Depression. It is unclear if oral selenium is beneficial for the treatment of prevention of depression. Details: A meta-analysis of observational research has found no difference in serum levels of selenium between patients with or without depression. In addition, serum levels of selenium do not correlate with depression scores (109091). A meta-analysis of clinical research shows that selenium supplementation, usually 100-200 mcg daily, modestly reduces symptoms of depression; however, at least one of the three studies included in this meta-analysis investigated the effects of selenium in patients with postpartum depression, specifically (109091). These meta-analyses are limited by the quality of included research and the small number of available studies.
• Diabetic nephropathy. It is unclear if oral selenium alleviates diabetic nephropathy symptoms. Details: A small clinical study in patients with diabetic nephropathy shows that taking selenium (Nature Made) 200 mcg daily for 12 weeks does not improve kidney markers such as blood urea nitrogen or serum creatinine when compared with placebo (97084).
• Dilated cardiomyopathy. There is limited evidence on the oral use of selenium in patients with Keshan disease and peripartum cardiomyopathy. Details: Observational research in patients with a specific type of dilated cardiomyopathy called Keshan disease and congestive heart failure has found that selenium supplementation is associated with a 61% decreased risk of cardiac death when compared with no supplementation (101346). A small clinical study in patients with peripartum cardiomyopathy and selenium deficiency shows that taking selenium 200 mcg daily for 3 months does not seem to improve heart failure symptoms or left ventricle systolic function, or prevent death, when compared with no treatment (104420).
• Esophageal cancer. Limited research suggests that oral selenium does not reduce esophageal cancer risk. Details: Low quality clinical research suggests that taking selenium supplements alone or with other vitamins does not decrease the risk of esophageal cancer when compared with control (4679,12185).
• Gastric cancer. Oral selenium has only been evaluated in combination with other ingredients and in a specific patient population; its effect when used alone and in other populations is unclear. Details: Population research in Chinese patients has found that high levels of selenium are associated with lower risk of gastric cancer and cancer mortality (97948). However, clinical research does not agree. A large clinical study in patients residing in China shows that taking selenium 37.5 mcg in combination with vitamin C 250 mg and vitamin E 100 IU twice daily for about 7.3 years does not reduce the risk of developing gastric cancer or precancerous gastric lesions when compared with placebo. This combination treatment was not associated with reduced gastric cancer incidence or mortality at the 14-year follow-up of this study (14447,51470). Another clinical study in healthy Chinese adults also shows that taking a combination of selenium 50 mcg, vitamin E 30 mg, and beta-carotene 15 mg daily for 5.2 years does not reduce the risk of gastric cancer when compared with control (4679). It is unclear if these findings are generalizable to populations in geographic locations other than China.
• Graves' ophthalmopathy. It is unclear if oral selenium is beneficial for Graves' ophthalmopathy. Details: A small clinical trial in adults with Graves' ophthalmopathy shows that taking selenium 100 mcg twice daily for 6 months is modestly beneficial for reducing disease activity, based on signs and symptoms including pain, swelling, and redness, when compared with placebo (109085).
• Hepatitis C. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with hepatitis C shows that taking a combination of selenium 200 mcg, vitamin C 500 mcg, and vitamin E 945 IU daily for 6 months does not have an effect on levels of alanine aminotransferase or viral load when compared with placebo (74377).
• HIV/AIDS. It is unclear if oral selenium improves outcomes in patients with HIV. Details: Clinical trials in HIV-positive men and women, most receiving anti-retroviral therapy (ART), shows that taking selenium 200 mcg daily for up to 2 years can reduce HIV-1 viral load, increase CD4 cell counts, and lower the risk of hospitalizations when compared with placebo (15266,74314). However, not all research agrees. Two small clinical trials in HIV-positive patients taking ART shows that taking selenium 100-200 mcg daily for 6-12 months does not reduce the risk for opportunistic infections and does not increase CD4 counts when compared with control (7830,104417). Furthermore, selenium does not seem to benefit patients that are not receiving conventional ART. A large clinical study in HIV-infected pregnant patients in Tanzania with poor access to ART shows that taking selenium 200 mcg daily with prenatal vitamins until 6 months after delivery, does not improve progression of HIV nor pregnancy outcomes when compared with no selenium supplementation (74419). Another large clinical study in HIV-infected and ART-naïve patients in Botswana shows that taking selenium 200 mcg daily for 24 months does not slow HIV progression when compared with placebo (92905).
• Hypertension. It is unclear if oral selenium improves blood pressure. Some evidence suggests selenium supplementation may slightly increase systolic blood pressure. Details: A meta-analysis of 5 small clinical studies in adults with various health conditions shows that taking selenium or selenium yeast 100-200 mcg/day for 6-12 weeks may increase systolic blood pressure by about 2 mmHg but does not impact diastolic blood pressure when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with preeclampsia, gestational diabetes, obesity, or heart failure. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
• Hyperthyroidism. It is unclear if oral selenium alleviates symptoms in patients with Graves' disease. Details: A small clinical study in patients with Graves' hyperthyroidism shows that taking sodium selenite 300 mcg daily in addition to treatment with methimazole for 24 weeks does not affect symptoms or recurrence rates when compared with placebo plus methimazole (97089). Oral selenium has also been studied in combination with other supplements. A small preliminary clinical trial in patients with newly diagnosed Graves' disease and low levels of selenium and vitamin D shows that taking selenium 100 mcg daily for 180 days along with vitamin D as cholecalciferol 7000 IU weekly for 270 days, in addition to methimazole, modestly reduces levels of serum free thyroxine and improves quality of life when compared with methimazole alone. However, taking selenium and vitamin D did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral selenium improves thyroid hormone balance in elderly individuals, pregnant patients, or patients with subclinical hypothyroidism. In patients with iodine deficiency, selenium supplementation may be harmful. Details: Low selenium levels or selenium deficiency seems to reduce conversion of thyroxine (T4) to triiodothyronine (T3). However, clinical research in healthy elderly patients is conflicting. Although one study shows that taking selenium 100 mcg daily for 3 months increases conversion of T4 to T3 when compared with placebo (17508), a larger study shows that taking selenium 100-300 mcg daily for 6 months does not impact conversion of T4 to T3 when compared with placebo (17509). Additionally, taking selenium can worsen hypothyroidism in people with iodine deficiency. People who are iodine- and selenium-deficient should not receive selenium supplements without concomitant iodine. In these individuals, selenium increases conversion of T4 to T3, but the thyroid gland lacks iodine to synthesize more T4 (1664,14563,14564,14565,17508). Selenium does not have a significant effect on thyroid function when iodine intake is adequate (1664,4844). In pregnant patients with hypothyroidism, clinical research shows that taking selenium does not reduce complications such as pre-eclampsia or preterm birth. However, selenium might improve postpartum thyroid function and decrease the risk of postpartum thyroiditis (17507). Also, taking selenium 200 mcg daily during pregnancy seems to reduce the risk of developing postpartum thyroid dysfunction and permanent hypothyroidism by 41% and 42%, respectively, when compared with placebo in euthyroid pregnant patients who are positive for thyroid peroxidase antibodies (74391). Selenium supplementation has also been studied for subclinical hypothyroidism. Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking selenium 83 mcg daily and myo-inositol 600 mg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared with baseline. Selenium and myo-inositol supplementation also reduced patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to selenium, myo-inositol, or the combination.
• Influenza. Although there is interest in using oral selenium for influenza, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Kidney failure. It is unclear if oral selenium is beneficial for improving lipid parameters in patients on hemodialysis. Details: Selenium levels may be low in patients undergoing chronic hemodialysis, and supplementation might be needed (1805,11053). However, clinical research in patients on hemodialysis shows that taking selenium daily for 3 months does not improve the lipid profile when compared with taking placebo (109095).
• Lichen planus. It is unclear if topical or oral selenium alleviates oral lichen planus symptoms. Details: A small clinical study in patients with oral lichen planus shows that applying a selenium hydrogel (selenomethionine 14 mcg/gram) twice daily for 6 weeks seems to significantly reduce pain at a 12 week follow-up, but not immediately after use, when compared with applying topical corticosteroids and antifungal agents 2-4 times daily. Taking oral selenium 200 mcg twice daily for 6 weeks seems to be no different than the topical corticosteroids and antifungal treatment at both time points (104422).
• Liver cancer. It is unclear if oral selenium reduces liver cancer risk. Details: Preliminary clinical research in China suggest that taking selenium 200 mcg daily for 2-5 years can reduce the incidence of liver cancer when compared with control (74389). The benefit of selenium on prevention of liver cancer in Western countries is unknown.
• Lymphedema. It is unclear if oral selenium reduces lymphedema complications. Details: Preliminary clinical research in patients with secondary lymphedema after breast cancer surgery shows that taking a sodium selenite solution 1000 mcg daily for 1 week followed by 300 mcg daily for 2 weeks and then 200 mcg daily for a total of 15 weeks might reduce recurrence of erysipelas, a type of bacterial skin infection, when compared with placebo (15334).
• Male infertility. It is unclear if oral selenium, used alone or in combination with other antioxidants, improves pregnancy or live birth rates for couples with idiopathic male infertility. Details: Meta-analyses of 2-3 clinical trials show that taking selenium, alone or in combination with other antioxidants, for 12-26 weeks modestly improves sperm count and motility when compared with placebo. However, pregnancy rates and live birth rates were only studied in one clinical trial each, with no statistical evidence of benefit (109094). Studies included in the analysis used selenium 26-200 mcg daily for 12-26 weeks, either alone or in combination with vitamin A 1 mg, vitamin C 10 mg, and vitamin E 15 mg; vitamin E 400 IU and folic acid 5 mg; lycopene 6 mg, vitamin E 400 IU, vitamin C 100 mg, zinc 25 mg, folate 0.5 mg, and garlic 1000 mg; or N-acetyl-cysteine 600 mg (74526,74493,102968,109094).
• Mercury toxicity. It is unclear if oral selenium improves clearance of mercury and reduces symptoms of toxicity. Details: A small clinical trial in Chinese adults environmentally exposed to high concentrations of mercury shows that taking selenium-enriched yeast, containing selenium 100 mcg, daily for 3 months increases urinary excretion of mercury when compared with control (90351).
• Muscular dystrophy. There is limited evidence on the oral use of selenium in Duchenne muscular dystrophy. Details: Preliminary clinical research suggests that supplementation with sodium selenite 1 mg daily for 6 months does not improve disease activity in patients with muscular dystrophy (74455).
• Obesity. It is unclear if oral selenium is beneficial for weight reduction. Details: A small clinical study in adults with obesity shows that taking selenium 240 mcg daily and following a low-calorie diet for 3 months is no different for weight reduction when compared with following a low-calorie diet alone (104416).
• Oral mucositis. It is unclear if oral selenium is beneficial for reducing oral mucositis in patients undergoing radiotherapy. Details: A small clinical study in patients with head and neck cancers shows that taking selenium 200 mcg twice daily for the duration of radiation therapy does not seem to reduce the incidence or severity of oral mucositis when compared with placebo (104421). It is unclear if other doses or routes of administration might be beneficial.
• Osteoarthritis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis shows that taking a specific selenium-containing combination supplement (Selenium-ACE) does not improve most clinical symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral selenium reduces ovarian cancer risk. Details: Epidemiological research has found that there is no association between dietary selenium intake and the risk of developing ovarian cancer (74342).
• Overall mortality. Although oral selenium does not seem to reduce overall mortality risk in most patients, it might have benefit in patients with low nutrient intake. Details: Meta-analyses of clinical research show that selenium supplementation, alone or in combination with other micronutrients, does not reduce all-cause mortality when compared with placebo (15305,90360,97078). Selenium might also not be beneficial when used in combination with non-nutrient supplements. An additional large clinical study in elderly patients in Sweden shows that taking selenium 200 mcg daily plus coenzyme Q10 100 mg twice daily for around 5 years does not reduce the risk of all-cause mortality when compared with placebo. The baseline selenium status of these patients is unclear (92904). Despite these results, some evidence suggests that selenium used with other nutrients might have benefit in patients with low nutrient intake. In a large clinical study, selenium in combination with zinc, vitamin C, vitamin E, and beta-carotene lowered all-cause mortality risk in men, but not women, when compared with control (14109). Researchers speculate that this result occurred because men have a lower intake of dietary antioxidants than women. Another large clinical study in Chinese patients with chronically low nutrient intake shows that taking selenium with beta-carotene and vitamin E decreases stroke mortality, cancer mortality, and total mortality when compared with control (2673).
• Pancreatic cancer. It is unclear if oral selenium reduces pancreatic cancer risk. Details: Some epidemiological research has found that increased selenium intake is associated with a 34% lower risk of pancreatic cancer (97093). However, other observational research has found no association (101342).
• Pancreatitis. Although there is interest in using oral selenium for pancreatitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Polycystic ovary syndrome (PCOS). It is unclear if oral selenium is beneficial for PCOS. Details: A small clinical study in patients with PCOS shows that taking selenium (Nature Made) 200 mcg daily for 8 weeks results in a significantly higher pregnancy rate of 19%, compared with 3% in those taking placebo. The incidences of alopecia and acne were reduced by 77% and 73%, respectively. There were also modest reductions in hirsutism severity and serum levels of high sensitivity C-reactive protein (hs-CRP) and dehydroepiandrosterone (DHEA); however, there was no effect on other hormone levels (109096). Another small clinical study in patients with PCOS undergoing in vitro fertilization shows that taking selenium yeast 200 mcg daily for 8 weeks improves measures of insulin sensitivity and reduces serum insulin and fasting blood glucose levels when compared with placebo. However, selenium supplementation does not improve the pregnancy rate or lipid parameters (110596). The effect of selenium supplementation on the live birth rate in this population is unclear. Selenium has also been studied in combination with other supplements for patients with PCOS. A small clinical study in adults with PCOS shows that taking selenium 200 mcg daily for 12 weeks, in conjunction with a combination probiotic product, modestly improves subjective scores of depression, anxiety, and stress when compared with placebo. Taking this combination also modestly reduces total testosterone levels and subjective ratings of hirsutism when compared with placebo (99659). It is not clear if these effects are due to selenium, the probiotic, or the combination.
• Postpartum depression. It is unclear if oral selenium is beneficial for postpartum depression. Details: A meta-analysis of two observational studies has found that a high selenium intake is associated with a modestly reduced risk of postpartum depression. The effect of selenium supplementation on symptoms of postpartum depression is unclear. One moderate-sized clinical trial included in this publication shows that taking selenium reduces symptoms of postpartum depression (109091).
• Pregnancy-induced hypertension. It is unclear if oral selenium reduces the development of hypertension during pregnancy. Details: A small clinical study in pregnant patients shows that drinking a dietary liquid containing selenium 100 mcg daily for 6-8 weeks seems to decrease the incidence of pregnancy-induced hypertension when compared with placebo (74481).
• Premature rupture of membranes (PROM). It is unclear if oral selenium during pregnancy prevents PROM. Details: One clinical trial shows that taking selenium 100 mcg daily from the first trimester of pregnancy until delivery significantly reduces the incidence of PROM to 13%, compared to 34% with placebo (109097).
• Radiation-induced diarrhea. It is unclear if oral selenium reduces diarrhea in patients receiving radiation therapy for cancer. Details: A small clinical study in patients with cervical or endometrial cancer shows that taking selenium 500 mcg on days of radiation therapy and 300 mcg on days without radiation therapy reduces the incidence of radiation-induced diarrhea to 20.5%, compared to 44.5% in the control group not taking selenium. This benefit appears to be more pronounced in patients receiving a larger (>1302 mL) planning target volume of radiation (90355).
• Rheumatoid arthritis (RA). It is unclear if oral selenium, as selenized yeast, reduces RA symptoms. Details: A small clinical study in patients with RA suggests that taking selenized yeast, providing selenium 200 mcg, daily for 90 days does not improve objective measures of RA when compared with placebo. However, there might be small improvements in quality of life measures (9763).
• Schizophrenia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with schizophrenia shows that taking a combination of selenium (Nature Made) 200 mcg and a combination probiotic mixture (LactoCare, Zisttakhmir Company) daily for 12 weeks modestly improves general positive and negative symptoms of schizophrenia, but not positive or negative scores, when compared with placebo. There were also modest improvements in levels of high-sensitivity C-reactive protein (CRP), fasting glucose, insulin resistance, and insulin sensitivity, but not lipid parameters (109087).
• Statin-induced myopathy. Small clinical studies suggest that oral selenium may not improve symptoms of myopathy in patients taking statins. Details: Small clinical studies in patients with statin-induced myopathy suggests that taking selenium (SelenoPrecise, Pharma Nord) 200 mcg daily with or without coenzyme Q10 for 3 months does not improve myopathy symptoms when compared with placebo (92908,92909).
• Stroke. It is unclear if intravenous selenium improves neurological outcomes following a stroke. Details: A small clinical trial in patients with a recent first ischemic stroke shows that intravenous sodium selenite pentahydrate (Selenase, Biosyn, Arzenitmittel GmbH) 2000 mcg after admission and then 1000 mcg daily for 5 days modestly improves some, but not all, measures of neurological deficits when compared with placebo (109088). Another small clinical trial in patients with a recent ischemic stroke shows that the same intervention improves some neurological outcome measures on day 7 or at an earlier discharge, but benefits were not maintained at 3 months (109093). The effects of oral selenium on neurological outcomes following a stroke have not been investigated.
• Succinylcholine-induced myalgia. It is unclear if oral selenium is beneficial for preventing succinylcholine-induced postoperative myalgia. Details: Clinical research in patients receiving succinylcholine for a sinuscopy shows that taking a single dose of selenium 200 mcg 2 hours before anesthesia induction modestly decreases the incidence of postoperative myalgia at 24 hours. In those taking selenium, 95% of patients had no postoperative myalgia, compared with 77.5% of those taking placebo. Postoperative analgesia requirements were also modestly reduced; however, there was no difference in overall pain or the incidence of muscle twitching (109089).
• Thyroid cancer. It is unclear if oral selenium reduces the risk of thyroid cancer in most patients. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and thyroid cancer risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer (102373). More recent observational research in postmenopausal individuals using data from the Women's Health Initiative has found that selenium intake at or above the recommended daily allowance from dietary sources or supplements is not associated with a decreased risk of thyroid cancer (110590).
• Ulcerative colitis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with ulcerative colitis shows that taking a liquid supplement containing a combination of selenium, fish oil, fructo-oligosaccharides, acacia, vitamin E, and vitamin C daily for 6 months does not improve disease activity scores when compared with placebo. However, taking the combination supplement seems to reduce the need for oral prednisone for symptom control (13757). The effect of selenium alone is unclear. More evidence is needed to rate selenium for these uses.

(Read more about SELENIUM)

POSSIBLY EFFECTIVE

• Osteoporosis. Higher dietary intakes of silicon in males and premenopausal females seem to be associated with higher bone mineral density (BMD), but it is unclear whether silicon supplements reduce the risk of osteoporosis. Details: Males and premenopausal females who have dietary intakes of silicon of at least 40 mg daily seem to have higher BMD than those with lower intakes. This could reduce the risk of osteoporosis (10470,12425). However, it is unclear if silicon supplements can reduce the risk for osteoporosis. Silicon intake has also been evaluated in postmenopausal females. Clinical and population-based research suggests that higher silicon intake does not seem to benefit postmenopausal females in general, although it may benefit those on hormone replacement therapy (10470,12425,75118,92135). Bone loss in postmenopausal females is primarily due to bone resorption. Silicon seems to affect only bone formation (12425).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral silicon is beneficial in patients with aging skin. Details: A small preliminary clinical study in healthy volunteers aged 40-60 years shows that taking a specific product (Exsynutriment by Biotec) containing organic silicon 600 mg in hydrolyzed marine collagen once daily, 15 minutes before breakfast, for 90 days improves skin firmness, hydration, and texture, but not wrinkles, brightness, or softness, when compared with placebo (100837).
• Alzheimer disease. Although there has been interest in using oral silicon for Alzheimer disease, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Androgenic alopecia. Although there has been interest in using oral silicon for androgenic alopecia, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral silicon for CVD, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Dental peri-implantitis. It is unclear if oral silicon is beneficial in patients with peri-implantitis. Details: A small, preliminary clinical study in patients aged 18-75 with peri-implantitis shows that a specific choline-stabilized orthosilicic acid product (BioSil, Bio Minerals NV) containing silicon 5 mg and choline 100 mg, taken twice daily for 12 months, does not improve markers of inflammation and periodontal disease (i.e. probing pocket depth, bleeding on probing) when compared with placebo (110028). However, this study may not have been adequately powered to detect a difference between groups. More evidence is needed to rate silicon for these uses.

(Read more about SILICON)

EFFECTIVE

• Thiamine deficiency. Oral thiamine prevents and treats thiamine deficiency syndromes. Details: Thiamine deficiency is treated with oral thiamine 5-30 mg daily as a single dose or in divided daily doses for one month. For severe deficiency, thiamine up to 300 mg daily can be used (15).Thiamine deficiency can occur in people with malabsorption conditions such as alcohol use disorder, cirrhosis, and gastrointestinal diseases; in those with inadequate intake due to anorexia, nausea, and vomiting; and in those with increased requirements, including pregnancy, increased carbohydrate intake, increased physical activity, hyperthyroidism, infection, and liver disease. However, deficiency is rare with these conditions (15). The elderly might also be at increased risk for subclinical thiamine deficiency (11076).
• Wernicke-Korsakoff syndrome (WKS). Parenteral thiamine is effective for treating symptoms of WKS. Details: Parenteral administration of thiamine 5-200 mg daily for 2 days decreases the risk of developing WKS and decreases symptoms of WKS in acute alcohol withdrawal. Between 30% and 80% of alcoholics are suspected to have thiamine deficiency (11075). An optimal dose for treating WKS has not been established; however, early research suggests that a 200 mg intramuscular dose may be more effective than lower doses (11075). In contrast, a moderate-sized clinical trial in adults with a history of heavy alcohol use who were asymptomatic or symptomatic for WKS shows that there is no benefit to administering high doses (300 mg 3 times daily) compared with medium (100 mg 3 times daily) or low (100 mg daily) doses of parenteral thiamine on cognitive or neurological functioning (111690). The study may have been inadequately powered to detect a difference between groups.

POSSIBLY EFFECTIVE

• Dysmenorrhea. Oral thiamine might reduce pain in some patients with dysmenorrhea. Details: A clinical study in adolescent Iranian females with dysmenorrhea shows that taking thiamine 100 mg alone or along with fish oil 500 mg daily for 2 months moderately reduces pain intensity and duration when compared with placebo (89341). Another preliminary clinical study in Indian females 12-21 years of age with moderate to severe primary dysmenorrhea shows that taking thiamine 100 mg daily for 90 days eliminates pain in 87% of participants when compared to baseline (77820). The validity of this finding is limited by the lack of a placebo group. Furthermore, available research was conducted in India and Iran, so it is unclear if these findings are generalizable to other geographic locations.

POSSIBLY INEFFECTIVE

• Coronary artery bypass graft (CABG) surgery. Intravenous thiamine does not seem to improve outcomes after CABG surgery. Details: A small clinical study in adults undergoing CABG surgery with cardiopulmonary bypass shows that giving intravenous thiamine 200 mg immediately prior to surgery and immediately after surgery does not improve clinical outcomes or lactate levels when compared with placebo (97010). Larger doses of thiamine also don't seem to be beneficial. Another small clinical study in patients receiving CABG with cardiopulmonary bypass shows that giving thiamine 600 mg intravenously on the day of surgery, and 400 mg daily for three postoperative days, does not improve postoperative outcomes when compared with placebo (103000).
• Heart failure. Most research suggests that oral or intravenous thiamine does not improve outcomes in patients with heart failure. Details: Observational research suggests that having heart failure is associated with 2.5-fold increased odds of having thiamine deficiency, possibly because of diuretic use, intestinal malabsorption, and metabolism changes. However, it is unclear if thiamine supplementation is beneficial. A meta-analysis of 2 small clinical trials in adults with systolic heart failure and unclear thiamine status shows that thiamine 200-300 mg given orally or by IV for 7-28 days improves left ventricular ejection fraction (LVEF) by 3% when compared with control (97012). However, other meta-analyses and clinical studies in adults with heart failure with or without thiamine deficiency show that taking intravenous, intramuscular, or oral thiamine 100-500 mg daily does not improve LVEF fraction, left ventricular end-diastolic volume, dyspnea, mortality, hospitalization, or exercise tolerance when compared with placebo or control (103002,111682,111686,111688).
• Mosquito repellent. Oral thiamine does not seem to repel mosquitos. Details: Clinical research in healthy volunteers shows that taking thiamine does not improve mosquito repellency when compared with taking vitamin C as a control (18016).
• Sepsis. Intravenous or oral thiamine, alone or in combination with vitamin C and hydrocortisone, does not seem to reduce mortality or prevent organ failure in sepsis or septic shock. Details: Multiple meta-analyses of small clinical studies in patients with septic shock show that intravenous or oral thiamine 100-500 mg 2-3 times daily for 3-7 days is no better than placebo for improving mortality, end-organ damage, number of ventilator-free days, and duration of intensive care unit (ICU) stay (105443,107717,107727,111689). One meta-analysis suggests that administration of thiamine alone increases the risk of mortality in these patients (111689). Subgroup analyses including only higher quality studies also fail to show a benefit of thiamine (107717). Another recent small clinical trial in patients with septic shock shows that receiving the same dose of intravenous thiamine does not increase vasopressor-free days when compared with placebo (105441). Intravenous thiamine 200 mg every 12 hours has also been evaluated in combination with intravenous vitamin C 1.5-2 grams and hydrocortisone 50-200 mg every 6-12 hours for 4-10 days (HAT therapy). While some retrospective research found HAT therapy to be beneficial (100315,102980,111689), high-quality, prospective clinical research has shown no benefit (105447,109956,111689). Meta-analyses in patients with sepsis and septic shock shows that receiving HAT therapy does not improve mortality, kidney injury, number of ventilator-free days, or ICU length of stay when compared with control (102129,104027,104028,104032,102998,105447,109956,111642,111689). Additionally, the meta-analyses suggest that HAT therapy does not reverse shock or improve sequential organ failure assessment (SOFA) scores (109556,111642). However, one meta-analysis found that HAT therapy shortened the duration of vasopressor use when compared with placebo (111642). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for immediate memory scores and development of posttraumatic stress disorder, HAT therapy was less beneficial when compared with placebo (111299).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral or intravenous thiamine is beneficial for treating or preventing AKI. Details: Observational research in adults admitted to the intensive care unit (ICU) with AKI has found that treatment with thiamine (dose unspecified) within the first 48 hours of admission is associated with 39% lower odds of in-hospital mortality and 28% higher odds of kidney function recovery when compared with patients that did not receive thiamine. Receiving thiamine was also associated with a 0.5-day reduction in ICU length of stay (107719).
• Anxiety. Although there is interest in using oral thiamine for anxiety, there is insufficient reliable information about the clinical effects of thiamine for this purpose.
• Cardiac arrest. It is unclear if intravenous thiamine reduces the risk of death after resuscitation from cardiac arrest. Details: A small clinical study in adults resuscitated from cardiac arrest shows that receiving intravenous thiamine 100 mg every 8 hours for 7 days does not reduce 28-day mortality when compare with a normal saline placebo (105442).
• Cardiovascular disease (CVD). It is unclear if oral thiamine is beneficial for treating or preventing CVD. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 16% increased odds of developing angina or myocardial infarction when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on CVD have not been studied (107725).
• Cataracts. Small studies suggest that increased dietary thiamine might help prevent cataracts. Details: Observational research has found that a high dietary intake of thiamine 10 mg daily is associated with 40% lower odds of nuclear cataracts (6378). Other population research has found that higher dietary intake of thiamine is associated with a modestly reduced risk of age-related lens opacification (14301).
• Cervical cancer. It is unclear if oral thiamine reduces the risk of developing cervical cancer. Details: Epidemiological research has found that increasing intake of thiamine from dietary and supplemental sources, along with folic acid, riboflavin, and vitamin B12, is associated with a lower odds of precancerous cervical lesions (11074).
• Child development. It is unclear if supplementing breastfeeding females with oral thiamine improves infant neurocognitive development. Details: Preliminary clinical research shows that supplementing breastfeeding females with oral thiamine, 1.2-10 mg daily for 22 weeks, starting at 2 weeks postpartum, does not improve most cognitive or neurodevelopmental scores in the child when compared with placebo. However, one subgroup analysis suggests that thiamine supplementation may improve language scores (107726).
• Cognitive function. Oral thiamine has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing thiamine hydrochloride 50 mg, other group B vitamins, bacopa, and ginkgo daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of the combination supplementation on measures of attention in those with an optimal diet at baseline (111334). It is unclear if these findings are due to thiamine, other ingredients, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if intravenous or oral thiamine improves clinical outcomes in patients hospitalized with COVID-19. Details: A small observational study of adults admitted to the intensive care unit with COVID-19 has found that treatment with intravenous or oral thiamine 100 mg daily for an average of 7 days is associated with a 63% reduction in the odds of death within 30 days when compared with control. However, there was no associated reduction in duration of hospitalization or mechanical ventilation (107721). In addition, a small observational study of adults with encephalopathy that were mechanically ventilated secondary to COVID-19 has found that taking thiamine 500 mg three times daily orally for 5 days improves neurological manifestations, including ophthalmoparesis and ataxia, when compared with baseline. The validity of this study is limited by the lack of a comparator group (107722).
• Critical illness (trauma). It is unclear if oral or intravenous thiamine is beneficial in patients with critical illness. Details: A meta-analysis of critically ill patients shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days does not affect the need for mechanical ventilation, duration of hospital stay, or mortality when compared with control (107727).
• Delirium. It is unclear if oral or intravenous thiamine helps to prevent or treat delirium. Details: In critically ill patients, a meta-analysis of clinical research shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days reduces the odds of developing delirium by 42% when compared with control (107727). However, some observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001). In non-critically ill, hospitalized adults with altered mental status, retrospective, observational research has also found that administration of oral or intravenous thiamine is not associated with improved cognitive function or reduced in-hospital mortality when compared with control (107723). Preliminary clinical research in adults undergoing an allogeneic hematopoietic stem cell transplant also shows that administering thiamine 200 mg three times a day intravenously for 7 days does not prevent delirium or shorten duration of delirium when compared with placebo (107718).
• Dementia. It is unclear if oral thiamine is beneficial for the prevention of dementia. Details: Observational research in patients with alcohol use disorder has found that taking thiamine is associated with a 24% to 46% lower risk of developing dementia when compared with not taking thiamine (102999).
• Depression. It is unclear if oral thiamine is beneficial in patients with depression. Details: Meta-analyses of population research in adults has found that high dietary consumption of thiamine is associated with a 10% to 31% lower risk of having depression when compared with low dietary consumption of thiamine. However, this research did not evaluate the effects of thiamine supplementation on depression (107133,107725). One small clinical study in adults with major depressive disorder shows that taking thiamine 300 mg daily in conjunction with fluoxetine 20 mg daily leads to greater improvements in depressive symptoms at 6 weeks when compared to fluoxetine with placebo. This benefit was no longer present at 12 weeks. This suggests that thiamine may accelerate improvement in symptoms during initiation of fluoxetine therapy (97013).
• Diabetes. It is unclear if oral thiamine is beneficial for type 2 diabetes or gestational diabetes. Details: A meta-analysis of 6 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not reduce glycated hemoglobin (HbA1c), fasting blood glucose, or postprandial blood glucose when compared with placebo (111681). A large, prospective cohort study in adults without type 2 diabetes suggests that the risk of new-onset diabetes is minimized in adults consuming thiamine 0.75-1.10 mg daily from the diet, while lower and higher thiamine intake levels are associated with an increased risk of new-onset diabetes (111685). Thiamine has also been studied for preventing gestational diabetes. A large, prospective cohort study in pregnant adults suggests that higher supplementation with thiamine during the first and second trimesters is associated with a lower risk of gestational diabetes when compared with lower levels of total thiamine intake. However, this effect was not found for dietary intake of thiamine, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic nephropathy. It is unclear if oral thiamine is beneficial for diabetic nephropathy. Details: A small clinical study in patients with early-stage diabetic nephropathy and microalbuminuria shows that taking thiamine 100 mg three times daily for 3 months decreases urinary albumin excretion, but does not affect glomerular filtration rate (GFR), when compared with placebo (16556).
• Diabetic neuropathy. Although there is interest in using oral thiamine for diabetic neuropathy, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Dry eye. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with dry eye suggests that adding unspecified doses of thiamine and mecobalamin to treatment with daily artificial tears and corticosteroid drops might slightly improve overall symptoms when compared with only artificial tears and corticosteroid drops for 1 month. There were no differences between groups at 2 months (105444). This finding is limited due to incomplete reporting and a lack of adjustment for multiple hypothesis testing.
• Dyslipidemia. It is unclear if oral thiamine is beneficial for treating or preventing dyslipidemia. Details: A meta-analysis of 3 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not improve low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides when compared with placebo (111681). Observational research in Korea suggests that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with 10% higher odds of developing dyslipidemia when compared with sufficient dietary thiamine intake. However, the effects of thiamine supplementation on dyslipidemia have not been studied (107725).
• Emergence delirium. It is unclear if intravenous thiamine helps to prevent emergence delirium in patients after surgery. Details: One clinical study in adults in the intensive care unit (ICU) after gastrointestinal surgery shows that receiving intravenous thiamine 200 mg daily for 3 days is associated with up to 84% lower odds of emergence delirium on the first two days, but not on the third day, when compared with a normal saline control (105440).
• Fatigue. It is unclear if oral thiamine is beneficial in patients with fatigue. Details: A small clinical crossover study in patients with chronic fatigue and inflammatory bowel disease (IBD) shows that taking thiamine 600-1800 mg daily for 20 days reduces fatigue scores when compared with placebo (105438). Taking oral thiamine 300 mg daily for an additional 12 weeks did not seem to affect fatigue scores when compared with placebo. However, an observational follow-up study found that those who self-continued thiamine for an additional 24 weeks after the study ended reported lower fatigue scores when compared with those who did not self-continue thiamine (107720).
• Glaucoma. Although there is interest in using oral thiamine for glaucoma, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Herpes zoster (shingles). It is unclear if subcutaneous thiamine is beneficial in patients with shingles. Details: A small clinical trial shows that receiving subcutaneous thiamine 100 mg injections six times weekly for 4 weeks reduces itching by at least 30% in 67% of patients with herpes zoster. However, thiamine does not appear to significantly reduce pain in most patients (90396).
• Hypertension. It is unclear if oral thiamine is beneficial in treating or preventing hypertension. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 5% increased odds of developing hypertension when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on hypertension have not been studied (107725).
• Impaired glucose tolerance (prediabetes). It is unclear if oral thiamine is beneficial in patients with prediabetes. Details: A very small clinical trial in patients with prediabetes shows that taking thiamine 100 mg by mouth three times daily for 6 weeks modestly decreases 2-hour postprandial plasma glucose levels when compared to baseline and decreases fasting blood glucose levels when compared with placebo (91168).
• Kidney failure. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary, low-quality, clinical research in adults with kidney failure undergoing regular hemodialysis shows that taking oral thiamine 90 mg daily with folic acid 30 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if this effect is due to thiamine, folic acid, or the combination.
• Migraine headache. It is unclear if dietary thiamine is beneficial for the prevention or treatment of migraine headache. Details: A large, retrospective, cross-sectional study suggests that higher dietary intake of thiamine is associated with lower odds of severe headache or migraine, especially in females (111684). The validity of these effects is limited by the subjective outcome measures and retrospective study design.
• Pneumonia. It is unclear if thiamine is beneficial for patients with pneumonia. Details: A large retrospective cohort study in adults hospitalized with pneumonia and active alcohol use disorder suggests that parenteral administration of thiamine is associated with reduced 14-day mortality and more frequent discharges home, but not a shorter length of stay or fewer ICU transfers, when compared with no thiamine use. Furthermore, parenteral thiamine doses above 200 mg do not appear to improve mortality but may be associated with longer length of stay and less frequent discharges home when compared with low oral doses of thiamine or parenteral thiamine at doses under 200 mg (111679). The validity of these effects is limited by the retrospective study design.
• Ventilator-associated pneumonia (VAP). It is unclear if oral or parenteral thiamine is beneficial for patients with VAP. Details: A retrospective study in adults with VAP in the intensive care unit (ICU) suggests that supplementation with intravenous or oral thiamine may be associated with reduced ICU and in-hospital mortality (111683). The validity of these effects is limited by the retrospective study design. More evidence is needed to rate thiamine for these uses.

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EFFECTIVE

• Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

POSSIBLY EFFECTIVE

• Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
• Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
• Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
• Measles. High-dose oral vitamin A seems to reduce mortality from measles in children under 2 years of age and may also reduce the incidence of measles in children up to 5 years of age. Details: Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502,95055,109755). However, in children with measles who are less than 2 years of age, taking vitamin A 200,000 IU orally for at least two doses seems to reduce mortality by up to 83% when compared with placebo (82373,82502). Also, taking vitamin A seems to reduce the incidence of measles in children ages 6 months to 5 years (95055,109755).
• Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
• Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
• Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). In 2010, a meta-analysis of 17 trials involving over 194,000 patients, showed that vitamin A supplementation reduces all-cause mortality by about 24% in children 6 months to 5 years of age (82559). However, some research published after this meta-analysis shows conflicting results (90773,90777). In fact, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which was published after the analysis and involved one million preschool children, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Furthermore, in 2017, a meta-analysis including the DEVTA trial along with 46 additional studies involving over 1.2 million preschool children, shows that vitamin A supplementation does reduce all-cause mortality by 12% when compared with control (95055). This meta-analysis was updated in 2022 with no additional studies or changes in conclusions (109755). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
• Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
• Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
• Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
• Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Still, some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A small study in adults over 40 years old with photodamaged skin shows that applying stabilized retinol 0.1% to the face daily for one year improves wrinkles and mottled pigmentation in over 50% of the participants when compared with a placebo treatment (104463).

POSSIBLY INEFFECTIVE

• Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
• Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
• Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
• Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
• Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
• Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
• Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.

LIKELY INEFFECTIVE

• Head and neck cancer. Oral vitamin A taken for 2 years does not seem to improve survival or prevent head and neck cancer recurrence. Details: A large clinical study n patients with a history of head and neck cancer shows that taking vitamin A as retinyl palmitate 300,000 IU daily for 1 year, and followed by 150,000 IU daily for another year, does not reduce the risk of second primary tumors or tumor recurrence when compared with placebo. Also, vitamin A does not seem to improve survival or event-free survival (1710).
• HIV transmission. Oral vitamin A does not reduce vertical HIV transmission risk. There is some concern that vitamin A might increase HIV transmission through breast milk. Details: Observational and intervention research shows that taking vitamin A orally does not decrease the risk of HIV transmission to the fetus during pregnancy, to newborns during delivery, or to infants during early breast-feeding (6376,82470,95059). Preliminary clinical research also shows that vitamin A supplementation of pregnant adults with HIV infection might increase the risk of HIV transmission to their babies through breast milk (9801).
• Lower respiratory tract infections. Oral vitamin A does not reduce the risk for lower respiratory tract infections in children. It is unclear if supplementation of oral vitamin A while breast-feeding reduces the risk of lower respiratory tract infections in nursing infants. Details: Taking vitamin A by mouth does not prevent or reduce symptoms of lower respiratory tract infections, such as cough and fever, in children (82288,82443). Furthermore, some research shows that vitamin A is associated with a slight increase in the risk of respiratory tract infections when administered to children with adequate nutritional status (82288). Additionally, one small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of febrile illness or respiratory tract infections in the nursing infants when compared with placebo (107293).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although prescription vitamin A analogs are approved to treat acne, it is unclear if non-prescription topical vitamin A products help with acne symptoms. Details: The high-dose vitamin A analogs adapalene (Differin) and tazarotene (Tazorac) are prescription drugs approved by the US Food and Drug Administration for the treatment of acne (103712,103713). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol, which have not been extensively evaluated in clinical research. A small preliminary clinical trial in adolescents and young adults with mild to moderate acne shows that applying topical benzoyl peroxide 2.5% each morning and a topical retinol plus salicylic acid product each evening for 12 weeks modestly improves acne severity and other measures of complexion when compared with baseline. All patients also used the same cleanser twice daily (109748). The validity of this finding is limited by the lack of a comparator group.
• Alcohol-related liver disease. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute alcoholic hepatitis shows that taking vitamin A in combination with coenzyme Q10 and other vitamins and minerals daily for 6 months does not improve survival when compared with placebo (61392).
• Asthma. It is unclear if oral vitamin A is beneficial for preventing asthma in children. Details: An observational study in children has found that higher dietary intake of vitamin A is associated with a lower risk of asthma. Children in the highest quartile of vitamin A intake (median of 2267 IU daily) at 7 years of age had improved lung function and 32% lower odds of asthma at 11-14 years of age when compared with children in the lowest quartile of vitamin A intake (median of 870 IU daily) (107291).
• Atopic dermatitis (eczema). It is unclear if supplementation of oral vitamin A while breast-feeding is beneficial for preventing eczema in nursing infants. Details: One small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of eczema in the nursing infants when compared with placebo (107293).
• Autism spectrum disorder. It is unclear if oral vitamin A is beneficial for improving symptoms of autism. Details: Children with autism spectrum disorder are at increased risk for vitamin A deficiency, and vitamin A levels have been inversely associated with autism symptoms. Preliminary clinical research shows that taking a single dose of vitamin A 200,000 IU slightly improves emotional response, communication, and other symptoms when compared to baseline (97168). The lack of a control group limits the validity of these findings. Another preliminary clinical study in children with autism and vitamin A deficiency shows that taking vitamin A 50,000 IU weekly for 6 months, but not as a single dose of 200,000 IU, seems to improve social impairment scores when compared with control. Controls were children with autism without vitamin A deficiency that did not take a supplement (104459).
• Breast cancer. Although vitamin A intake has been associated with a reduced risk for breast cancer, it is unclear if vitamin A supplements are beneficial. Details: Epidemiological evidence has found an association between high intake of vitamin A and a reduced risk of breast cancer. A meta-analysis of epidemiological research has found that the adults with the highest intake of vitamin A, either from diet alone or also from supplements, reduces the odds of developing breast cancer by 16% when compared with the lowest intake (1444,34610,109752). However, the effects of supplemental vitamin A, specifically, are unclear.
• Cataracts. It is unclear if oral vitamin A is beneficial for cataract prevention. Details: A large-scale population-based study has found that high dietary intake of vitamin A is associated with a reduced risk of nuclear cataracts (6378). Also, other population research has found that the highest dietary intake of vitamin A is associated with a 17% lower risk of cataracts when compared with the lowest intakes (90786). However, there is conflicting evidence regarding the association between blood levels of vitamin A and the risk of cataracts (90786,90944). It is not known if supplemental vitamin A is beneficial.
• Cervical cancer. It is unclear if oral vitamin A is beneficial for cervical cancer prevention. Details: A meta-analysis of clinical research shows that increased vitamin A levels in the blood or higher vitamin A intakes are associated with a reduced risk of cervical cancer. However, this effect is observed when both forms of vitamin A, either retinol or carotenoids, are considered. When only the retinol form is considered, vitamin A supplementation does not seem to reduce the risk of cervical cancer (34613,109752). Also, a meta-analysis of epidemiological research has found that vitamin A intake, either from diet alone or supplements, does not affect the risk of cervical cancer (109752).
• Chemotherapy-induced diarrhea. It is unclear if oral vitamin A helps to prevent diarrhea caused by chemotherapy. Details: A very small clinical study in children receiving chemotherapy shows that taking vitamin A orally does not seem to prevent GI adverse effects, including diarrhea and mouth pain, when compared with control (9802).
• Child development. Oral vitamin A might improve growth and development in children with vitamin A deficiency, but not in those with good nutritional status. Details: Supplementing with vitamin A 60 mg for up to 9 years does not promote or improve child growth in children with appropriate nutritional status (20132). However, in children with vitamin A deficiency, supplementation with vitamin A may improve growth (82246).
• Chronic obstructive pulmonary disease (COPD). There is limited evidence on the oral use of vitamin A in patients with emphysema. Details: Observational research has found that consuming recommended amounts of vitamin A in the diet is associated with 33% lower odds of developing emphysema (103678).
• Colorectal adenoma. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination supplement containing selenium, zinc, vitamin A, vitamin C, and vitamin E orally daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by about 40% when compared with placebo in patients with large-bowel adenomas (92903). It is not clear if this benefit is due to vitamin A or other constituents.
• Colorectal cancer. It is unclear if oral vitamin A is beneficial for colorectal cancer prevention. Details: Taking vitamin A alone or in combination with beta-carotene does not seem to reduce the risk of colorectal cancer (12185).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin A improves recovery after CABG surgery. Details: Preliminary clinical research shows that taking vitamin A 5000 IU daily (as retinol palmitate) for 21 days starting on the day of CABG surgery reduces time in intensive care after surgery by 46% to 69% compared to a control group not given vitamin A (90783). Supplementation with vitamin A also improves total hospitalization time for those patients with adequate zinc status (90783).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin A is beneficial for the treatment of mild to moderate COVID-19. Details: Clinical research in COVID-19 outpatients treated with hydroxychloroquine shows that taking vitamin A 25,000 IU daily for 10 days modestly reduces the number of patients with symptoms of fever, body ache, and fatigue when compared with placebo. However, there was no effect on the number of patients with cough, shortness of breath, lack of appetite, chest pain, diarrhea, loss of smell, or headache (109745).
• Depression. It is unclear if oral vitamin A is beneficial for depression. Details: A meta-analysis of observational research has found that dietary intake of vitamin A is inversely associated with depression. The highest intake of vitamin A was associated with a 17% reduced risk of depression when compared with the lowest intake. Also, vitamin A intake was lower in individuals with depression (109743). The effect of vitamin A supplementation is unclear.
• Esophageal cancer. It is unclear if oral vitamin A is beneficial for esophageal cancer prevention. Details: Observational research has found that higher beta-carotene and vitamin A intake is associated with a reduced risk of esophageal cancer (34551,103675). However, evidence from higher-quality clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of esophageal cancer (12185).
• Gastric cancer. It is unclear if oral vitamin A is beneficial for gastric cancer prevention. Details: Taking vitamin A alone and in combination with beta-carotene does not seem to reduce the risk of gastric cancer (12185).
• Glaucoma. It is unclear if oral vitamin A is beneficial for glaucoma prevention. Details: A meta-analysis of observational research has found that a high dietary intake of vitamin A is associated with a 37% reduced risk of glaucoma when compared with a low intake (109742).
• HIV/AIDS. It is unclear if oral vitamin A is beneficial for improving HIV/AIDs outcomes. Details: A meta-analysis of clinical trials and population research shows that maternal vitamin A supplementation of mothers with poor vitamin A status at baseline does not influence child or maternal mortality, hospitalization rate, or HIV/AIDS progression. However, pediatric vitamin A supplementation seems to decrease mortality rates in children with HIV/AIDS when compared with placebo (34529,95059).
• HIV/AIDS-related diarrhea. It is unclear if oral vitamin A is beneficial for preventing diarrhea associated with HIV. Details: A large clinical trial shows that taking vitamin A can decrease the rate of diarrhea-specific mortality by up to 92% in vitamin A-deficient children with or without HIV/AIDS (1465). However, a meta-analysis of clinical research shows that taking vitamin A does not significantly reduce diarrhea-specific mortality when only children with HIV/AIDS are considered (82511). But vitamin A does appear to reduce overall mortality in these children by 50% to 63% (1465,82511).
• Human papillomavirus (HPV). It is unclear if topical or oral vitamin A is beneficial for the resolution of genital warts caused by HPV. Details: A meta-analysis of small clinical trials in patients with genital warts suggests that the oral prescription drugs isotretinoin and etretinate might promote resolution of warts when compared with baseline. However, the topical prescription drug tretinoin 0.05% cream does not seem to help (104460). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Infant development. It is unclear if intramuscular vitamin A improves the development of low birth weight infants. Details: A meta-analysis of clinical research shows that giving intramuscular vitamin A to very low birth weight infants reduces the risk of chronic lung disease at 36 weeks postmenstrual age by about 13% compared to control (95053). Preliminary clinical research also shows that giving intramuscular vitamin A along with inhaled nitric oxide gas for 3 weeks to low birth weight infants on mechanical ventilation might improve mental development at one year in some of these patients when compared with inhaled nitric oxide gas alone (90778). However, a meta-analysis of clinical research shows that intramuscular vitamin A does not improve neurodevelopment in very low birth weight infants (95053).
• Iron deficiency anemia. It is unclear if oral vitamin A is beneficial for the prevention or treatment of anemia due to iron deficiency. Details: Some research in children and pregnant adults without anemia shows that taking vitamin A increases plasma levels of hemoglobin and ferritin, and may reduce the risk of developing anemia (9518,34627). However, another study in pregnant patients, half of whom had anemia at baseline and half of whom did not have anemia, shows that taking 3000 mcg retinol orally in combination with iron and folate does not improve hemoglobin or erythropoietin concentrations when compared with taking iron and folate (9188). In preterm infants with existing anemia, taking vitamin A 5000 IU and vitamin B complex 40 mg daily improves serum ferritin, hemoglobin, and reticulocyte levels and reduces the need for blood transfusions when compared with taking either vitamin alone. Taking vitamin A alone, however, does not improve these outcomes (100330).
• Leukemia. It is unclear if oral vitamin A is beneficial for leukemia prevention. Details: Preliminary clinical research in adults with chronic myelogenous leukemia shows that taking a specific vitamin A product (Aquasol, Armour Pharmaceuticals) 50,000 IU orally daily in combination with busulfan therapy does not significantly increase progression-free survival or overall survival when compared with busulfan alone. Furthermore, supplementation with vitamin A plus busulfan seems to increase the percentage of patients who experience grade 2 toxicity by about 5-fold when compared with busulfan alone (82652).
• Liver cancer. It is unclear if oral vitamin A is beneficial for liver cancer prevention. Details: Population research has found that vitamin A supplementation or serum levels of vitamin A are not associated with the risk of liver cancer (97169).
• Lung cancer. It is unclear if oral vitamin A is beneficial for lung cancer treatment or prevention. Details: Population research has found that increased dietary intake of vitamin A is not associated with a reduced risk of lung cancer (35628). Furthermore, supplementation with vitamin A and beta-carotene seems to increase the risk of lung cancer in smokers or those exposed to asbestos (2642,34675). A large clinical trial in patients with existing lung cancer shows that vitamin A 300,000 IU daily for one year followed by 150,000 IU daily for a second year does not increase survival (1710). However, some clinical research shows that high-dose vitamin A 300,000 IU daily following curative lung cancer resection reduces the risk of new primary tumors in patients heavily exposed to tobacco (7875).
• Malaria. It is unclear if oral vitamin A is beneficial for reducing symptoms of malaria in young children. Details: Taking vitamin A orally seems to help decrease symptoms of malaria in children less than 3 years of age living in endemic areas (1464). However, other clinical research shows that single doses of vitamin A 100,000 to 200,000 IU do not improve coma resolution, convulsions, fever, parasite clearance, or mortality in infants and children less than 5 years of age with cerebral malaria (90785).
• Multiple sclerosis-related fatigue. It is unclear if oral vitamin A is beneficial for reducing fatigue in patients with multiple sclerosis. Details: Preliminary clinical research in patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a shows that taking vitamin A 25,000 IU (as retinyl palmitate) (Zahravi Pharmaceutical) daily for 6 months followed by 10,000 IU daily for 6 months, improves physical, cognitive, and psychosocial fatigue when compared with placebo (95052).
• Necrotizing enterocolitis (NEC). A meta-analysis of several small clinical trials suggests that intramuscular vitamin A does not seem to prevent NEC. Details: A meta-analysis of 3 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 1500-5000 IU every other day or three times weekly for 28 days does not reduce the risk of NEC when compared with a control (107297).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin A is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that intake of vitamin A at levels above 2330 mcg daily is associated with a 17% lower risk of non-Hodgkin lymphoma when compared with those whose daily intake of vitamin A is less than 642 mcg per day (90945).
• Nonmelanoma skin cancer. It is unclear if oral vitamin A is beneficial for nonmelanoma skin cancer prevention. Details: Observational research over 26 years found that higher dietary vitamin A intake is associated with a 12% reduced risk for cutaneous squamous cell carcinoma in healthy patients when compared with lower vitamin A intake (101673).
• Oral clefts. It is unclear if oral vitamin A is beneficial for oral cleft prevention. Details: A meta-analysis of observational research has found that periconceptional use of vitamin A, from diet and/or supplements, is associated with a 13% reduced incidence of cleft lip alone or with a cleft palate, but is not associated with the risk of cleft palate alone, in the child (109751).
• Osteoarthritis. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with osteoarthritis shows that taking a specific product containing vitamin A in combination with selenium, vitamin C, and vitamin E (Selenium ACE, Carls-Berghs Farmaceutiska AB) does not appear to alleviate symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral vitamin A is beneficial for ovarian cancer prevention. Details: Most observational research has found that increased dietary intake of vitamin A is associated with a reduced risk of developing ovarian cancer (9193,103679,109752). The most recent meta-analysis of epidemiological research has found that adults with the highest intake of vitamin A, either from diet alone or supplements, reduces the odds of developing ovarian cancer by 19% when compared with the lowest intake (109752).
• Pancreatic cancer. It is unclear if oral vitamin A is beneficial for pancreatic cancer prevention. Details: A meta-analysis of observational research has found that higher intake of vitamin A is associated with a reduced risk of pancreatic cancer; however, this benefit appears to be limited to only hospital-based cases and studies conducted in Europe (95060). In contrast, a meta-analysis of clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of pancreatic cancer (12185).
• Parkinson disease. It is unclear if oral vitamin A prevents Parkinson disease development. Details: Population research has found that blood levels or dietary intake of vitamin A are not associated with the risk of Parkinson disease (91164).
• Photoreactive keratectomy. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking a specific product (Evitex capsules, Alcon) containing vitamin A along with vitamin E seems to improve healing after photoreactive keratectomy. High dose (50,000 to 75,000 IU) vitamin A in the form of retinol palmitate taken daily with vitamin E (alpha-tocopheryl nicotinate) 460-590 mg daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity in patients undergoing laser surgery for myopia (348).
• Pneumonia. Oral vitamin A does not seem to prevent mortality related to pneumonia in children. However, it is unclear if vitamin A reduces symptom severity and hospitalization in children. Details: Clinical research in children living in developing countries shows that taking vitamin A orally does not prevent mortality related to pneumonia (1466,82362,82504,82717,109749). However, the evidence related to symptom duration and severity is mixed. A large study and early meta-analyses show that vitamin A does not prevent pneumonia or decrease the severity or length of hospitalization in children with pneumonia (1466,82362,82504,82717). A more recent meta-analysis also shows that giving vitamin A to children at or below 5 years of age does not affect the duration of hospitalization (109755). The best evidence to date comes from a recent meta-analysis of randomized clinical trials. This meta-analysis shows that, when given in combination with conventional therapy to children up to 10 years of age, vitamin A reduces the duration of symptoms including fever, cough, lung rale, and shortness of breath, as well as the duration of hospitalization and time to a negative X-ray, when compared with conventional therapy alone (109749). However, the number of trials evaluating each endpoint is small and more research is needed to confirm these findings.
• Prematurity. It is unclear if vitamin A reduces the duration of hospitalization for premature infants. Details: A meta-analysis of four randomized controlled trials in preterm infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the duration of hospitalization when compared with placebo (109750).
• Prostate cancer. It is unclear if oral vitamin A is beneficial for prostate cancer prevention. Details: Observational studies suggest that dietary intake of vitamin A is not associated with a reduced risk of prostate cancer (14134).
• Psoriasis. It is unclear if topical vitamin A is beneficial for psoriasis symptoms. Details: The vitamin A analog tazarotene (Tazorac) is a prescription drug that is approved by the U.S. Food and Drug Administration to treat stable plaque psoriasis covering up to 20% body surface area (103713). This drug is not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Radiation proctopathy. It is unclear if oral vitamin A is beneficial for reducing chronic radiation proctopathy symptoms. Details: A small clinical study in patients experiencing chronic radiation proctopathy caused by pelvic radiotherapy shows that taking retinol palmitate 10,000 IU daily for 90 days might reduce rectal symptoms when compared with placebo (82350).
• Retinopathy of prematurity. Most small studies show that oral or intramuscular vitamin A does not reduce the risk of retinopathy of prematurity (ROP). Details: A meta-analysis of 4 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 2000-10,000 IU every other day or three times weekly, or oral vitamin A 2000 IU daily, for 28 days does not reduce the risk of ROP when compared with a control (107297). Another meta-analysis of clinical research shows that providing supplemental enteral vitamin A 1500 IU or an average of 5000 IU daily, starting within four days of birth, does not reduce the incidence of severe ROP (109750,109753). However, a very small clinical study in preterm infants, which was not included in the meta-analysis, shows that receiving retinol palmitate drops 3000 IU/kg daily for 28 days reduces the risk of ROP by 88% when compared with no treatment (103672).
• Urinary tract infections (UTIs). It is unclear if adding oral vitamin A to antibiotic therapy is beneficial for symptoms of acute pyelonephritis in young females. Details: A small clinical study in females 2-12 years of age with a first occurrence of acute pyelonephritis shows that taking vitamin A 1500 units/kg daily for 10 days in conjunction with antibiotics decreases the duration of fever by about 1.3 days and reduces urinary frequency by about 1.5 episodes per day when compared to taking placebo with antibiotics. Taking vitamin A might also reduce the occurrence of moderate or severe renal scarring after 6 months when compared with placebo (100327). The validity of these findings is limited by small study size and a high dropout rate.
• Warts. It is unclear if topical or oral vitamin A improves the resolution of viral warts. Details: A meta-analysis of observational and clinical research in patients with viral warts suggests that receiving prescription oral retinoids (isotretinoin, acitretin, etretinate) seems to produce a 61% rate of wart resolution. Prescription topical retinoids seems to produce a 64% rate of wart resolution (104461). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol. More evidence is needed to rate vitamin A for these uses.