Alpha Lipoic + by Wonder Laboratories

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

• 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)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111554).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

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POSSIBLY SAFE ...when used orally and appropriately. Alpha-lipoic acid has been used with apparent safety in doses of up to 2 grams daily for 3 months to 2 years. Lower doses of 600 mg daily have been used with apparent safety for up to 4 years (3540,3541,3542,20479,96449,97630,101867,101869,103327,103333)(103335,104651,104660). ...when used topically and appropriately. A cream containing alpha-lipoic acid 5% has been used with apparent safety in clinical trials lasting up to 12 weeks (12021). ...when given intravenously and appropriately. Intravenous alpha-lipoic acid has been used safely in doses of up to 6000 mg weekly in clinical trials lasting up to 3 weeks (3540,3557,10148,12106).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Alpha-lipoic acid has been used with apparent safety in doses of up to 600 mg daily for 3 months in children aged 10-17 years (103330).

CHILDREN: POSSIBLY UNSAFE
when used orally in amounts over 600 mg daily. At least five cases of alpha-lipoic acid intoxication have been reported for children aged 14 months to 16 years who consumed alpha-lipoic acid at doses up to 226 mg/kg (approximately 2400 mg). Symptoms of alpha-lipoic acid-induced intoxication included seizures, acidosis, vomiting, and unconsciousness (90444,96227,96234,104653).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Alpha-lipoic acid has been used safely during pregnancy at doses up to 600 mg daily for up to 4 weeks (96222).

LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Chromium has been safely used in doses up to 1000 mcg daily for up to 6 months (1934,5039,5040,6858,6859,6860,6861,6862,6867,6868)(7135,7137,10309,13053,14325,14440,17224,90057,90061)(90063,94234,95095,95096,95097,98687); however, most of these studies have used chromium doses in a range of 150-600 mcg. The Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, long-term. Chromium has been safely used in a small number of studies at doses of 200-1000 mcg daily for up to 2 years (7060,7135,42618,42628,42666,110605,110607,110609). However, the Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

CHILDREN: LIKELY SAFE
when used orally and appropriately in amounts not exceeding the daily adequate intake (AI) levels by age: 0-6 months, 0. 2 mcg; 7-12 months, 5.5 mcg; 1-3 years, 11 mcg; 4-8 years, 15 mcg; males 9-13 years, 25 mcg; males 14-18 years, 35 mcg; females 9-13 years, 21 mcg; females 14-18 years, 24 mcg (7135). POSSIBLY SAFE...when used orally and appropriately in amounts exceeding AI levels. Chromium 400 mcg daily has been used safely for up to 6 weeks (42680).

PREGNANCY: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for pregnancy is 28 mcg daily for those 14-18 years of age and 30 mcg daily for those 19-50 years of age (7135).

PREGNANCY: POSSIBLY SAFE
when used orally in amounts exceeding the adequate intake (AI) levels. There is some evidence that patients with gestational diabetes can safely use chromium in doses of 4-8 mcg/kg (1953); however, patients should not take chromium supplements during pregnancy without medical supervision.

LACTATION: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for lactation is 44 mcg daily for those 14-18 years of age and 45 mcg daily for those 19-50 years of age (7135). Chromium supplements do not seem to increase normal chromium concentration in human breast milk (1937). There is insufficient reliable information available about the safety of chromium when used in higher amounts while breast-feeding.

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LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111551,111554).

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

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

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ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the antioxidant effects of alpha-lipoic acid might alter the effectiveness of alkylating agents.  Details The use of antioxidants like alpha-lipoic acid during chemotherapy is controversial. There are concerns that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as alpha-lipoic acid have on chemotherapy. Advise patients to consult their oncologist before using alpha-lipoic acid.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, alpha-lipoic acid may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro, alpha-lipoic acid inhibits platelet aggregation (98682).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking alpha-lipoic acid with antidiabetes drugs might increase the risk of hypoglycemia.  Details Although some small clinical studies have suggested that alpha-lipoic acid can lower blood glucose levels (3545,3874,3875,3876,20490,20493,104650), larger clinical studies in patients with diabetes have shown no clinically meaningful effect (20494,20495,20496,90443,90445,110118). Additionally, co-administration of single doses of alpha-lipoic acid and glyburide or acarbose did not cause detectable drug interactions in healthy volunteers (3870).

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the antioxidant effects of alpha-lipoic acid might alter the effectiveness of antitumor antibiotics.  Details The use of antioxidants like alpha-lipoic acid during chemotherapy is controversial. There are concerns that antioxidants could reduce the activity of antitumor antibiotic drugs, which work by generating free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as alpha-lipoic acid have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using alpha-lipoic acid.

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, alpha-lipoic acid might decrease the effects of thyroid hormone drugs.  Details Animal research suggests that co-administration of thyroxine with alpha-lipoic acid reduces conversion into the active T3 form (8946).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, chromium may have additive effects with antidiabetic agents and increase the risk of hypoglycemia.  Details Some research shows that taking chromium might lower blood glucose levels, especially in patients with poorly controlled type 2 diabetes (7137,14440,15169,94234,95097,95098,98687).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, aspirin might increase chromium absorption.  Details Animal research suggests that aspirin may increase chromium absorption and chromium levels in the blood (21055).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of chromium and insulin might increase the risk of hypoglycemia.  Details In clinical research, chromium has been shown to increase insulin sensitivity (1952,14440,95095),

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Chromium might bind levothyroxine in the intestinal tract and decrease levothyroxine absorption.  Details Clinical research in healthy volunteers shows that taking chromium picolinate 1000 mcg with levothyroxine 1 mg decreases serum levels of levothyroxine by 17% when compared to taking levothyroxine alone (16012). Advise patients to take levothyroxine at least 30 minutes before or 3-4 hours after taking chromium.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D NSAIDs might increase chromium levels in the body.  Details Drugs that are prostaglandin inhibitors, such as NSAIDs, seem to increase chromium absorption and retention (7135).

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General ...Alpha-lipoic acid appears to be generally well tolerated when used orally, intravenously, or topically.
Most Common Adverse Effects:
Orally: Headache, heartburn, nausea, and vomiting.
Topically: Irritation and rash.
Intravenously: Nausea and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about insulin autoimmune syndrome (IAS).

Cardiovascular ...Orally, hypotension has been reported rarely in a clinical trial (104650).

Dermatologic ...Orally, skin rash and itching have been reported after use of alpha-lipoic acid (16391,20490,21674,96233,104650). Topically, alpha-lipoic acid can cause local irritation, including burning, stinging, mild rash, or contact dermatitis (12021,30836,111701). In one case, an 86-year-old female developed allergic contact dermatitis with severe itching and oozing after applying alpha-lipoic acid 5% cream to her lower extremities. The patient had a positive skin patch test for alpha-lipoic acid, confirming the causative agent (111701). In another case, a 47-year-old female developed contact dermatitis characterized by a pruritic rash and labial adhesions hours after applying a 5% vulvar serum containing lipoic acid 0.9 grams, vitamin E, vitamin C, hyaluronic acid, and retinol palmitate to the vulva to treat vulvar lichen sclerosis. Testing confirmed that the causative agent was alpha-lipoic acid (111704). Intravenously, local allergic reactions have occurred at the injection site (1547).

Endocrine ...Orally, at least 50 published cases of insulin autoimmune syndrome (IAS) thought to be associated with use of alpha-lipoic acid have been reported (16392,104656,104657,104658,104659,107893,112941). Most reported cases have been associated with alpha-lipoic acid supplements or enriched foods; IAS has not been reported with intake of alpha-lipoic acid in food. IAS has been linked to compounds, such as alpha-lipoic acid, that contain sulfhydryl groups, but it is unclear if taking alpha-lipoic acid with other drugs known to trigger IAS increases the risk (107893,112941). IAS is characterized by very high serum insulin levels and high titers of autoantibodies against endogenous insulin. Sulfhydryl groups interact with disulfide bonds of insulin, increasing its immunogenicity (112941). Symptoms include severe spontaneous hypoglycemic episodes, as well as hunger and neuroglycopenic symptoms such as blurred vision, weakness, confusion, dizziness, sweating, and palpitations (104656,104657,107893,112941). Time to onset of IAS ranges from 1 week to 4 months (107893). Most cases of IAS have been reported in Japan and have occurred in individuals with the human leucocyte antigen (HLA)-DRB1*04:06 allele (16392,104656,107893). For patients of European decent, cases of IAS have mainly occurred in individuals with the HLA-DRB1*04:03 allele (104656,104658,104659,107893). This suggests that either of these alleles might produce a genetic predisposition to alpha-lipoic acid-associated IAS. Reported doses of alpha-lipoic acid have ranged from 200-800 mg daily, most commonly 600 mg daily (104656,104658,104659,107893). IAS-related hypoglycemic episodes have been treated with oral or intravenous glucose or sucrose, as well as prednisone. Episodes decline following discontinuation of alpha-lipoic acid, and insulin values normalize within 3-9 months (104656,104658,104659,107893).

Gastrointestinal ...Orally, heartburn, nausea, and vomiting have been reported after use of alpha-lipoic acid (3557,12106,16391,20475,30844,96225,101868,103327,103328,103333)(103335,104650,104654,104655). Higher doses (1200-1800 mg daily) seem to cause more severe effects than lower doses (600 mg daily) (3557,20475,30844,96225). Alpha-lipoic acid may also cause a burning sensation from the throat to the stomach, abdominal discomfort, or bitter taste when used orally (20478,20490,21664,96225). Intravenously, alpha-lipoic acid can cause gastrointestinal upset, including nausea and vomiting. Adverse effects are more common in patients receiving higher intravenous doses (3557) and may be more common in the elderly (96225).

Genitourinary ...Orally, alpha-lipoic acid may cause urinary disorders (20479). Oral alpha-lipoic acid has also been associated with a change in urine odor (96225,103327).

Neurologic/CNS ...Orally, alpha-lipoic acid may cause headache (21664,103328,104655) or dizziness (104650).
Intravenously, paresthesias have been reported to worsen temporarily at the beginning of therapy. Also, intravenous alpha-lipoic acid can cause headache. Adverse effects are more common in patients receiving higher intravenous doses (3557).

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General ...Orally, chromium is generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal irritation, headaches, insomnia, irritability, mood changes.
Serious Adverse Effects (Rare):
Orally: Rare cases of kidney and liver damage, rhabdomyolysis, and thrombocytopenia have been reported.

Dermatologic ...Orally, chromium-containing supplements may cause acute generalized exanthematous pustulosis (42561), skin rashes (42679), and urticaria (17224). Also, chromium picolinate or chromium chloride may cause systemic contact dermatitis when taken orally, especially in patients with contact allergy to chromium (6624,90058). In one clinical study, a patient taking chromium nicotinate 50 mcg daily reported itchy palms that improved after the intervention was discontinued. It is unclear of this effect was due to the chromium or another factor (95096).
Topically, hexavalent chromium, which can be present in some cement, leather products, or contaminated soil, may cause allergic contact dermatitis (42645,42789,90060,90064,110606).
A case of lichen planus has been reported for a patient following long-term occupational exposure to chromium (42688).

Endocrine ...Orally, cases of hypoglycemia have been reported for patients taking chromium picolinate 200-1000 mcg daily alone or 200-300 mcg two or three times weekly in combination with insulin (42672,42783). Chromium picolinate has also been associated with weight gain in young females who do not exercise and in those following a weight-lifting program (1938).

Gastrointestinal ...Orally, chromium in the form of chromium picolinate, chromium polynicotinate, chromium-containing brewer's yeast, or chromium-containing milk powder may cause nausea, vomiting, diarrhea, decreased appetite, constipation, flatulence, or gastrointestinal upset (14325,42594,42607,42622,42643,42679).
Long-term exposure to heavy metals, including chromium, has been associated with increased risk of gallbladder disease and cancer (42682,42704).

Genitourinary ...Orally, chromium polynicotinate has been associated with disrupted menstrual cycles in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Hematologic ...Anemia, hemolysis, and thrombocytopenia were reported in a 33 year-old female taking chromium picolinate 1200-2400 mcg daily for 4-5 months (554). The patient received supportive care, blood product transfusions, and hemodialysis and was stabilized and discharged a few days later. Lab values were normal at a one-year follow-up.

Hepatic ...Liver damage has been reported for a 33-year-old female taking chromium picolinate 1200 mcg daily for 4-5 months (554). Also, acute hepatitis has been reported in a patient taking chromium polynicotinate 200 mcg daily for 5 months (9141). Symptoms resolved when the product was discontinued. Two cases of hepatotoxicity have been reported in patients who took a specific combination product (Hydroxycut), which also contained chromium polynicotinate in addition to several herbs (13037).

Musculoskeletal ...Acute rhabdomyolysis has been reported for a previously healthy 24-year-old female who ingested chromium picolinate 1200 mcg over a 48-hour time period (42786). Also, chromium polynicotinate has been associated with leg pain and paresthesia in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Neurologic/CNS ...Orally, chromium picolinate may cause headache, paresthesia, insomnia, dizziness, and vertigo (6860,10309,14325,42594). Vague cognitive symptoms, slowed thought processes, and difficulty driving occurred on three separate occasions in a healthy 35-year-old male after oral intake of chromium picolinate 200-400 mcg (42751). Transient increases in dreaming have been reported in three patients with dysthymia treated with chromium picolinate in combination with sertraline (2659). A specific combination product (Hydroxycut) containing chromium, caffeine, and ephedra has been associated with seizures (10307). But the most likely causative agent in this case is ephedra.

Psychiatric ...Orally, chromium picolinate has been associated with irritability and mood changes in patients taking the supplement to lose weight, while chromium polynicotinate has been associated with agitation and mood changes in patients taking the supplement to prevent weight gain during smoking cessation (6860,42643).

Renal ...Orally, chromium picolinate has been associated with at least one report of chronic interstitial nephritis and two reports of acute tubular necrosis (554,1951,14312). Laboratory evidence suggests that chromium does not cause kidney tissue damage even after long-term, high-dose exposure (7135); however, patient- or product-specific factors could potentially increase the risk of chromium-related kidney damage. More evidence is needed to determine what role, if any, chromium has in potentially causing kidney damage.
Intravenously, chromium is associated with decreased glomerular filtration rate (GFR) in children who receive long-term chromium-containing total parenteral nutrition - TPN (11787). Topically, burns caused by chromic acid, a hexavalent form of chromium, have been associated with acute chromium poisoning with acute renal failure (42699). Early excision of affected skin and dialysis are performed to prevent systemic toxicity.

Other ...Another form of chromium, called hexavalent chromium, is unsafe. This type of chromium is a by-product of some manufacturing processes. Chronic exposure can cause liver, kidney, or cardiac failure, pulmonary complications, anemia, and hemolysis (9141,11786,42572,42573,42699). Occupational inhalation of hexavalent chromium can cause ulceration of the nasal mucosa and perforation of the nasal septum, and has been associated with pneumoconiosis, allergic asthma, cough, shortness of breath, wheezing, and increased susceptibility to respiratory tract cancer and even stomach and germ cell cancers (42572,42573,42601,42610,42636,42667,42648,42601,42788,90056,90066). Although rare, cases of interstitial pneumonia associated with chromium inhalation have been reported. Symptoms resolved with corticosteroid treatment (42614).

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

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

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

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

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

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

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

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

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

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

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

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