Diabetic Support - Circulation & Metabolism Support by GNC Women's Ultra Mega

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)

EFFECTIVE

• L-carnitine deficiency. Oral and intravenous L-carnitine can treat primary and secondary L-carnitine deficiency. Details: Administering L-carnitine orally or intravenously is effective for acute or chronic treatment of primary L-carnitine deficiency or secondary L-carnitine deficiency due to inborn errors of metabolism. This is an FDA-approved indication for L-carnitine (4949,58611,59018). For primary or secondary deficiencies, oral L-carnitine 990 mg 2-3 times daily is used. For inborn errors of metabolism resulting in secondary L-carnitine deficiency, L-carnitine 50 mg/kg given as a slow (2-3 minute) bolus injection or by infusion followed by 50 mg/kg administered in divided doses every 3-4 hours over the next 24 hours is also used. Subsequent daily maintenance doses of intravenous L-carnitine are usually around 50 mg/kg (3616).

POSSIBLY EFFECTIVE

• Angina. Oral and intravenous L-carnitine may improve exercise tolerance and symptoms of angina during exercise in patients with angina. Details: Several small clinical trials in patients with chronic stable angina or cardiac syndrome X show that taking L-carnitine orally or intravenously seems to improve exercise tolerance and time to onset of angina when compared with placebo (3623,3624,58156,59096,59118,59216,59217,59230). Oral doses of L-carnitine have ranged from 900 mg to 2 grams daily in single or divided doses for 2 weeks to 6 months (3623,3624,58156,59096,59118,59217). Intravenous L-carnitine 3 grams in 500 mL of 5% dextrose, administered once daily for 14 days (59230), or intravenous DL-carnitine 40 mg/kg administered 30 minutes prior to exercise (59216) have also been used.
• Congestive heart failure (CHF). Oral and intravenous L-carnitine may improve exercise capacity and symptoms of heart failure in patients with CHF. Details: Several small clinical trials in patients with CHF show that taking L-carnitine 1.5-3 grams daily in single or divided doses for up to 34 months or administering intravenous L-carnitine 5 grams daily for 7 days seems to improve symptoms and increase exercise capacity when compared with placebo (3625,3626,58145,58771,58824). Also, taking a specific combination product containing L-carnitine 2250 mg and coenzyme Q10 270 mg (Carni Q-Gel, Tishcon Corporation) daily for 12 weeks appears to improve symptoms of CHF when compared with no treatment (58392).
• Hyperlipidemia. Oral or intravenous L-carnitine may slightly improve lipid levels. Oral, but not intravenous, L-carnitine may also improve lipoprotein(a) levels in patients with elevated lipoprotein(a). Details: Most meta-analyses of clinical research in patients with or without hyperlipidemia show that L-carnitine, given orally at a dose of 76 mg to 3 grams daily or intravenously at a dose of 15-20 mg/kg three times weekly, appears to reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels by up to 9.5 mg/dL, 8.3 mg/dL, and 11.2 mg/dL, respectively, while increasing high-density lipoprotein (HDL) cholesterol by up to 1.6 mg/dL. Sub-analyses in patients with elevated levels of specific lipids shows that L-carnitine might be most beneficial in these populations (95073,102019,111886). However, clinical research is generally very low to moderate quality. Also, any effects of L-carnitine on these lipids are modest and might not be considered clinically significant. An umbrella meta-analysis of meta-analyses of clinical research shows that taking L-carnitine orally reduces total cholesterol, LDL cholesterol, and triglyceride levels by only 1.1 mg/dL, 4.8 mg/dL, and 2.5 mg/dL, with increases in HDL cholesterol of 0.7 mg/dL (111896). More information is needed on the effects of L-carnitine on lipid levels specifically in patients with hyperlipidemia. Some research has also evaluated the benefits of L-carnitine in people with hyperlipidemia and elevated lipoprotein(a) levels or those undergoing hemodialysis. Preliminary clinical research and a meta-analysis of clinical research in these populations shows that taking L-carnitine 1-2 grams daily for 8-24 weeks reduces levels of lipoprotein(a) by about 9 mg/dL when compared with control (58155,95073). However, giving L-carnitine intravenously 1 gram three times weekly or 4 grams daily does not improve lipoprotein(a) levels in these patients (95073). Also, oral or intravenous L-carnitine does not improve LDL cholesterol, HDL cholesterol, or triglyceride levels in these patients (58155,95073). Whether L-carnitine reduces the risk of cardiovascular events in patients with hyperlipidemia is unknown.
• Kidney failure. Intravenous, but not oral, L-carnitine is FDA-approved for the prevention and treatment of L-carnitine deficiency in patients with kidney failure undergoing hemodialysis. Any other benefits with the use of L-carnitine in patients on hemodialysis are unclear. Details: Patients with kidney failure undergoing maintenance hemodialysis often experience L-carnitine deficiency, which can lead to lipid, red blood cell, cardiac muscle, and skeletal muscle abnormalities (26496). Use of intravenous L-carnitine for the prevention and treatment of L-carnitine deficiency in people with kidney failure who are undergoing hemodialysis is an FDA-approved indication for L-carnitine. L-carnitine 10-20 mg/kg is given as a slow (2-3 minute) bolus injection, with dose adjustments made based on subsequent pre-dialysis L-carnitine concentrations (3616). However, oral L-carnitine is not FDA-approved for this purpose. There is concern that long-term administration of high doses of oral L-carnitine may result in accumulation of toxic metabolites, including trimethylamine and trimethylamine-N-oxide, in patients with kidney failure (3616). Research in other areas are conflicting. Most clinical research shows that taking L-carnitine 0.7-3 grams or 10 mg/kg daily or administering L-carnitine 2-6 grams or 30-60 mg/kg weekly via intravenous infusion can improve cardiac function, intravenous fistula complications, red blood cell count, hemoglobin, and C-reactive protein levels in patients on hemodialysis (9790,26496,58257,58437,58842,59009,59178,111877). A meta-analysis of 18 clinical studies in adults with kidney-related anemia undergoing hemodialysis shows that receiving oral or intravenous L-carnitine reduces erythropoietin responsiveness and erythropoiesis stimulating agent (ESA) requirement, but not hemoglobin level, when compared with placebo or conventional therapy, regardless of treatment duration or route of administration (107406). Despite an earlier meta-analysis suggesting that L-carnitine does not reduce the incidence of dialysis-related hypotension or muscle cramping (58511), a more recent meta-analysis shows that L-carnitine reduces the incidence of dialysis-related hypotension by 74% when compared with placebo (111878). However, sub-analyses suggest that only oral L-carnitine, and doses of over 4.2 grams weekly for at least 12 weeks, are effective for preventing hypotension (111878). A meta-analysis and some preliminary clinical research also show that muscle cramping is reduced by up to 78% when compared with controls (104176,111878). Additionally, observational research has found that administering at least 1 gram of L-carnitine per dialysis session for at least 10 sessions monthly is associated with a 10% to 20% decrease in the number of hospitalization days during the subsequent month (58409). However, L-carnitine may not be beneficial for improving other measures in people with kidney failure receiving dialysis. While some research shows that L-carnitine decreases lipoprotein(a) levels (44187), low-density lipoprotein (LDL) cholesterol levels (26496,91723,107399), and total cholesterol levels (107399), most research shows that it does not improve serum lipid levels (9790,26496,44187,58257,58320,58842,58939,59009,59025,59031)(59036,59059,59080,90633,91723,107399). Additionally, while one small clinical trial shows that taking L-carnitine can improve performance on some exercise tests (104179), most research shows that L-carnitine does not improve respiratory function or exercise performance. The effect on quality of life is unclear (58154,58437,58472,58743,59031,90633,111867,111877).
• Male infertility. Oral L-carnitine, taken alone or in combination with acetyl-L-carnitine, may increase sperm motility in males with infertility, leading to a greater likelihood of pregnancy in female partners. Details: Although some clinical research has yielded conflicting results (58209,58588,59020,90627,111861), most clinical research shows that taking L-carnitine 1-3 grams daily in divided doses for up to 24 weeks, with or without acetyl-L-carnitine 1 gram daily, increases sperm count and motility, and improves sperm morphology, in males with infertility of various etiologies (12352,58167,58182,58194,58334,58469,58831,58849,59129,59189)(59190,101560,107394,111861,111459,111888,111890). However, it is unclear if taking L-carnitine increases the odds of pregnancy. One meta-analysis of randomized controlled trials shows that taking L-carnitine and acetyl-L-carnitine in combination increases the odds of pregnancy by 3.7-fold over placebo. However most clinical research investigating the effect of L-carnitine alone or with acetyl L-carnitine on pregnancy rates disagrees (12352,58182,101560,111861,111459,111888). The number of studies investigating the effect of L-carnitine alone or with acetyl-L-carnitine on pregnancy rate is small and the duration of supplementation may be inadequate. Taking L-carnitine 1 gram and acetyl-L-carnitine 0.5 grams twice daily after taking nonsteroidal anti-inflammatory drugs for 2 months seems to increase sperm count and motility in males with abacterial prostatovesiculoepididymitis, an inflammation of the prostate gland, seminal vesicles, and epididymis (9791). Some studies have also evaluated L-carnitine in combination with other ingredients. One clinical trial in males with asthenospermia shows that taking L-carnitine 150 mg, acetyl-L-carnitine 50 mg, L-arginine 1660 mg, and Panax ginseng 200 mg daily for 3 months increases sperm motility and sexual satisfaction when compared with no treatment (32189). Another small clinical trial shows that taking this combination along with prulifloxacin 600 mg daily for 6 months improves sperm concentration and motility when compared with prulifloxacin alone in patients with chronic prostatitis due to Chlamydia trachomatis infection (59006). Other small and preliminary clinical studies have investigated the effects of a specific combination product providing L-carnitine 1 gram twice daily for 6 months, along with acetyl-L-carnitine, coenzyme Q10, selenium, zinc, vitamin C, folic acid, vitamin B12, and citric acid (Proxeed Plus). Taking this combination product has been shown to improve measures of sperm quality such as sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. The effect on sperm volume and morphology is unclear. Most research has been conducted in patients with oligoasthenozoospermia, although some benefit has also been shown in patients with varicocele-related infertility, especially those with more severe varicocele (102017,107395,111296). The validity of these findings is limited by the lack of comparator group. Also, it is unclear if these effects are due to L-carnitine, other ingredients, or the combination. The effect of L-carnitine in combination with other ingredients on pregnancy rate has also been examined. One meta-analysis of moderate-quality clinical research shows that taking L-carnitine in combination with micronutrients increases the odds of pregnancy by 3.5-fold over placebo or no treatment (111888).
• Myocarditis. Oral DL-carnitine may prevent myocarditis in children with diphtheria. Details: Myocarditis is a complication of diphtheria. Clinical research in children with diphtheria shows that taking DL-carnitine 100 mg/kg daily for 4 days reduces the risk of myocarditis and mortality when compared with no treatment (3620,3621).
• Valproic acid-induced toxicities. Although more well-designed research is needed to confirm these findings, oral and intravenous L-carnitine may improve neurologic and hepatic function and reduce ammonia levels in patients with these valproic acid-induced toxicities. Details: Valproic acid-induced toxicities are often associated with low plasma and tissue levels of L-carnitine. Preliminary clinical research and case reports in patients on valproic acid therapy who have neurologic or hepatic deterioration or hyperammonemia show that taking L-carnitine 50-100 mg/kg daily in divided doses or administering L-carnitine 150-500 mg/kg daily via intravenous infusion seems to improve neurologic and hepatic function and bring plasma ammonia levels within normal limits (1438,1914,1915,1916,1917,4523,5798,5799,95068). There is also some preliminary evidence that intravenous L-carnitine can prevent the development of severe valproic acid-induced hepatotoxicity when given to patients being treated for overdose and accidental ingestion of valproic acid (1438,4528,5798,5799), especially if treatment is initiated early (4528). Despite these results, most evidence consists of anecdotal individuals or small case series. A more recent retrospective cohort study suggests that treatment with an L-carnitine dosing regimen consisting of a 100 mg/kg intravenous loading dose followed by up to 3 grams daily in divided doses for 3 days or until ICU discharge does not enhance valproic acid elimination or prevent organ dysfunction when compared with patients not treated with L-carnitine (111869). Also, taking L-carnitine does not appear to reduce valproic acid-associated weight gain (58295). Well-designed clinical trials are still needed to determine the role of L-carnitine in the treatment or prevention of valproic acid toxicities.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in patients with mild-to-moderate acne shows that applying a proprietary formulation containing L-carnitine, licochalcone, and 1,2-decanediol to the face twice daily for 8 weeks reduces the number of acne lesions and pustules and improves quality of life when compared to baseline. However, the improvements do not appear to be significant when compared with placebo (26493).
• Age-related fatigue. Small clinical studies suggest that oral L-carnitine may improve physical and mental fatigue associated with aging. Details: Two small clinical trials in elderly patients experiencing fatigue after slight physical activity shows that taking L-carnitine 2-4 grams daily for 1-6 months improves physical and mental fatigue, increases muscle mass, and decreases fat mass when compared with placebo (16109,16111).
• Aluminum phosphide poisoning. It is unclear if intravenous L-carnitine is beneficial in people with aluminum phosphide poisoning. Details: A meta-analysis of preliminary clinical research in patients with aluminum phosphide poisoning shows that intravenous L-carnitine does not reduce the odds of mortality when compared with control groups receiving routine treatments only (111892). However, only 2 studies were included in the analysis and both studies may have been underpowered to detect differences.
• Alzheimer disease. Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking L-carnitine tartrate 3.73 grams, in combination with serine, nicotinamide riboside, and N-acetyl cysteine, daily for 28 days and then twice daily for 56 days does not improve cognitive function when compared with taking placebo. However, in patients with the most severe symptoms, there was some modest improvement (110623). This study may have been underpowered to detect differences. Also, the effect of L-carnitine alone is unclear.
• Androgenic alopecia. It is unclear if topical L-carnitine is beneficial in people with androgenic alopecia. Details: One small clinical trial in individuals with androgenic alopecia shows that applying topical L-carnitine 2% solution to the scalp twice daily for 6 months significantly increases the number of terminal hair shafts on the scalp when compared with placebo (58390).
• Anorexia nervosa. Although there has been interest in using oral L-carnitine for anorexia nervosa, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Anthracycline cardiotoxicity. Oral and intravenous L-carnitine have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with breast cancer undergoing doxorubicin treatment shows that taking a combination of L-carnitine and vitamin E over 4 21-day treatment cycles decreases the proportion of patients with cardiac events by 24.2% when compared with chemotherapy treatment only. There were also modest beneficial effects on some enzyme measures of cardiac health. Patients received L-carnitine 3 grams intravenously on the first day of each cycle followed by an oral intake of 300 mg 4 times daily for the remaining 20 days. Vitamin E 1800 mg daily was taken orally in 3 divided doses (111891).
• Athletic performance. Oral L-carnitine has been evaluated for its effect on athletic performance in several small and short-term clinical studies, with mixed results. Details: Maximal exercise in trained athletes has been associated with a decrease in plasma L-carnitine levels (3648,58583). Theoretically, restoring these levels with L-carnitine supplementation might have beneficial effects. However, clinical studies examining the use of L-carnitine for athletic performance have reported conflicting results. Some clinical studies show that taking L-carnitine 2 grams, either before exercise or daily for up to 6 weeks, enhances athletic performance and endurance and reduces post-exercise muscle pain in male athletes and healthy untrained males (58450,59182,59185), but other studies do not support these findings (1947,59128,59134). Additionally, although some studies show that taking L-carnitine 1-2 grams or 40 mg/kg before exercise or 4 grams daily for 2 weeks can decrease lactate accumulation and increase oxygen uptake, power output, and time to anabolic threshold during exercise (3649,3650,59061,59184,59186), other studies show no improvement in these outcomes (58471,58775,59033,59045,59069,59128). These discrepancies may be related to the small study sizes, short treatment durations, and variable dosing regimens.
• Atrial fibrillation. It is unclear if oral L-carnitine is beneficial for preventing postoperative atrial fibrillation in patients undergoing aortic valve surgery. Details: A very small clinical study in patients undergoing aortic valve replacement or valve-sparing aortic root replacement shows that receiving oral L-carnitine (L-Cartin FF, Otsuka Pharmaceutical) 1 gram three times daily, beginning 2 days prior to surgery and continuing for 7 days after surgery, is associated with a postoperative atrial fibrillation rate of 20%, compared with a rate of 60% in a historical age-matched control group not receiving L-carnitine (107408).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral L-carnitine is beneficial in children with ADHD. Details: One small crossover trial in children with ADHD shows that taking L-carnitine 50 mg/kg twice daily for 6 months improves parent and teacher assessments of behavior when compared with placebo (58166).
• Autism spectrum disorder. Small clinical studies suggest that oral L-carnitine may improve some symptoms of autism spectrum disorder. Details: Small clinical trials in children 3-16 years of age with autism spectrum disorder show that taking L-carnitine 50 mg/kg or 150 mg/kg daily for 8 to 12 weeks modestly improves overall symptoms of autism, especially lethargy, social isolation, hyperactivity, and irritability, when compared with taking placebo. However, there is inconsistency between studies with respect to rating scales used and specific endpoints showing improvement. In one study, children remained on any pre-existing medications; in the other two, all children were also taking risperidone (58981,111887,111900).
• Arrhythmia. Small clinical studies suggest that oral L-carnitine may reduce the incidence of arrhythmias in patients with premature ventricular contractions. Details: Small clinical trials in patients with premature ventricular contractions show that taking L-carnitine 2 grams twice daily for 45 weeks or 2 grams three times daily for 2 weeks might reduce the incidence of arrhythmias when compared to baseline (59043,59120,59143).
• Asthenopia (eye strain). Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in videoterminal users with computer vision syndrome and without dry eye shows that taking a product containing L-carnitine 50 mg, along with zinc and extracts of elderberry, black currant, and eleuthero root (Meramirt CM) daily for 1 month modestly reduces severity of eye strain and sensitivity when compared with not taking this product (111295). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Beta-thalassemia. Small clinical studies suggest that oral L-carnitine may improve symptoms and reduce complications of beta-thalassemia minor, intermedia, and major. Details: Several small clinical trials in children with beta-thalassemia major show that taking L-carnitine 50 mg/kg daily for 3-6 months might reduce pulmonary artery systolic pressure, increase cardiac output during exercise, and improve progression to puberty (58294,58502,58556). Clinical research in adults with beta-thalassemia intermedia shows that taking L-carnitine with hydroxyurea appears to increase hemoglobin and hematocrit and reduce left ventricular end-diastolic diameter, a measure of pulmonary hypertension (58679). In patients with beta-thalassemia major or intermedia aged 6 years and up, taking L-carnitine 50 mg/kg daily for 6 months normalized left ventricular dilatation and hypertrophy in 30% and 37% of patients, respectively, compared with only 10% in those taking placebo. Cardiac output was also improved, but there were no changes in blood parameters (101565). Clinical research in children with beta-thalassemia minor shows that taking L-carnitine 50 mg/kg daily, with or without folic acid 1 mg daily, for 3 months appears to reduce bone pain by 84% to 87% and increase the number of climbable stairs 3.1- to 5.2-fold when compared with baseline (90631).
• Cachexia. Small clinical studies suggest that oral L-carnitine may improve body composition and quality of life in patients with cancer-related cachexia. Details: One small clinical trial in patients with cancer-related cachexia shows that taking L-carnitine 4 grams daily for 12 weeks increases body mass index (BMI) when compared with placebo (59029). Other research shows that taking L-carnitine 4 grams daily with megestrol acetate, eicosapentaenoic acid (EPA), and thalidomide for 5 months is more effective than any single product alone for increasing lean body mass in patients with cancer-related cachexia (23437). Additionally, taking L-carnitine 4 grams daily with megestrol acetate, celecoxib, and antioxidants for 4 months appears more effective than megestrol acetate alone for improving lean body mass, fatigue, and quality of life in these patients (59012).
• Cancer-related fatigue. It is unclear if oral L-carnitine is beneficial for improving fatigue in patients with advanced cancer. Details: Some cancer patients have low blood levels of L-carnitine, which may reduce energy production and lead to fatigue. Some small clinical trials in patients with advanced cancer show that taking L-carnitine 3-4 grams daily for 7 days significantly improves some measures of fatigue when compared to baseline (16106,16110). However, other higher quality clinical research shows that taking L-carnitine 2-4 grams daily for 4-12 weeks is no more effective than placebo for improving fatigue in advanced cancer patients (26498,58523,59029).
• Celiac disease. It is unclear if oral L-carnitine is beneficial in patients with celiac disease. Details: Some research shows that L-carnitine blood levels are low in patients with celiac disease. One small clinical trial in patients with celiac disease shows that taking L-carnitine 2 grams daily for 6 months lowers some measures of fatigue when compared with placebo. However, L-carnitine does not significantly improve measures of depression or quality of life in these patients (16105).
• Chemotherapy-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with fatigue due to sunitinib therapy. Details: A small clinical study in adults with renal cell carcinoma who are experiencing fatigue associated with sunitinib treatment shows that taking L-carnitine 1500 mg daily for 2 weeks modestly improves fatigue severity when compared to baseline (100352). The validity of this finding is limited by the small study size and lack of a comparator group.
• Chronic fatigue syndrome (CFS). It is unclear if oral L-carnitine is beneficial in patients with CFS. Details: One small clinical study in adults with CFS shows that taking L-carnitine 1 gram three times daily for 2 months can improve some symptoms of CFS when compared to baseline (3630). The validity of this finding is limited by the lack of a comparator group.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral L-carnitine is beneficial in patients with COPD. Details: One small clinical study in adults with moderate to severe COPD shows that taking L-carnitine 2 grams daily for 6 weeks improves exercise performance and walking tolerance when compared with placebo (58213).
• Cirrhosis. Preliminary research suggests that oral L-carnitine may be beneficial in patients with cirrhosis. Details: One small clinical trial in patients with cirrhosis who are receiving branched-chain amino acids supplements to improve nutritional status shows that taking L-carnitine 1 gram orally daily for 6 months, in addition to increasing exercise by 2000 steps per day, does not improve muscle volume, handgrip strength, or leg strength, but does reduce complaints of muscle cramping, when compared to baseline (102124). Another small, uncontrolled clinical trial in patients with cirrhosis shows that taking L-carnitine 1800 mg daily for 6 months does not improve Child-Pugh scores, but may improve quality of life, when compared to baseline (104177). The validity of these studies is limited by the lack of comparator groups. The effect of L-carnitine has also been examined retrospectively in patients with cirrhosis. One retrospective study in matched patients that had been admitted to hospital for cirrhosis suggests that taking L-carnitine for more than 30 days is associated with an increase in survival length by about 21 months compared with not taking L-carnitine. Overall, L-carnitine use was also associated with a 36% to 48% increase in the proportion of patients surviving 1-5 years, with the greatest effect in patients with modest to severe liver dysfunction. The median dose of L-carnitine was 1000 mg daily for at least 6 months is associated with a reduced loss of skeletal muscle compared with not taking L-carnitine (111860). The validity of these studies is limited by their retrospective design.
• Cognitive function. It is unclear if oral L-carnitine is beneficial for improving cognitive function in healthy individuals. Details: Low-quality clinical research shows that taking L-carnitine 500 mg as a single dose or 250 mg twice daily for 3 days does not improve cognitive function or memory in otherwise healthy young adults when compared with placebo (58176,95070).
• Coronary heart disease (CHD). It is unclear if oral L-carnitine is beneficial in patients with CHD. Details: One small clinical trial in patients with CHD shows that taking L-carnitine 2 grams prior to exercise does not improve endurance when compared with placebo (58196). Another small clinical trial in patients with CHD shows that taking L-carnitine 1 gram daily for 12 weeks does not improve low-density lipoprotein (LDL) cholesterol, total cholesterol, or apolipoprotein-B when compared with placebo; however, it does appear to increase high-density lipoprotein (HDL) and apolipoprotein A-1 levels in these patients (95071).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral L-carnitine is beneficial for COVID-19 prevention or treatment. Details: Preliminary clinical research in patients hospitalized with mild to moderate COVID-19 shows that taking L-carnitine 1 gram 3 times daily for 5 days does not reduce the incidence of fever or cough when compared with standard treatments only. However, all patients taking L-carnitine survived compared with 86% of those given standard treatment only. Also, there were improvements in oxygen saturation and inflammatory measures (111874). Other clinical research in patients with confirmed asymptomatic or mild COVID-19 shows that taking L-carnitine tartrate (Carnipure) 1 gram 3 times daily for 21 days does not prevent the development of severe lung symptoms when compared with taking placebo. However, in a sub-group of patients, lung lesion improvement was significantly better between days 7 and 14. In adults without COVID-19 but living with someone with confirmed disease, taking this product does not prevent COVID-19 when compared with taking placebo. However, the total number of confirmed illnesses in the population was low (111898).
• Critical illness (trauma). It is unclear if oral or nasogastric L-carnitine is beneficial for critical illness. Details: One small clinical trial in critically ill patients in the ICU shows that receiving L-carnitine (BSK, Zist Takhmir Co, Tehran-Iran) 3 grams daily via a nasogastric tube for 7 days modestly improves disease severity, organ function, inflammatory and other laboratory measures when compared with receiving placebo. Also, mortality rate was reduced by approximately 50%. There was no effect on the duration of hospital or ICU stay (111883,111884). However, another small clinical trial in critically ill patients following an acute ischemic stroke shows that oral or nasogastric L-carnitine tartrate 500 mg every 8 hours for 6 days does not affect the duration of mechanical ventilation or hospital or ICU stay, the severity of illness, or 28-day mortality rates, when compared with taking placebo. There was a modest beneficial effect on insulin resistance (111881). This study was small and may have been underpowered to detect differences.
• Diabetes. Oral L-carnitine may improve glycemic control in patients with diabetes, but it is unclear if these improvements are clinically meaningful. It is also unclear if L-carnitine can improve lipid profiles or weight loss in these patients. Details: While individual study results are mixed (58169,58189,58514,58793,90632,96922,101561), meta-analyses of available clinical research in mixed populations shows that taking L-carnitine 200 mg to 4 grams daily reduces fasting plasma glucose and glycated hemoglobin (HbA1C) levels, and possibly insulin, and improves insulin resistance, when compared with taking placebo or a control diet, although the clinical significance of these improvements is unclear (102018,111875,111886). One meta-analysis shows that these benefits are generally specific to patients with high levels of fasting glucose, diabetes, or obesity, as well as studies investigating L-carnitine in doses of at least 2 grams daily for 12 weeks. However, a small number of studies included in this analysis investigated the effects of acetyl-L-carnitine (111875). Other research in obese patients with type 2 diabetes shows that, when taken with orlistat or sibutramine, L-carnitine 2 grams daily for 12 months decreases body weight and body mass index and improves glycemic control when compared with orlistat or sibutramine alone (58778,58830,58882). The effect of L-carnitine on lipids in people with diabetes is unclear. Some studies show significant reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and/or lipoprotein(a) (58554,58647,58649,90632,101561,107397), while other studies show no improvement in lipid profiles (58169,58189).
• Dilated cardiomyopathy. Small clinical studies suggest that oral L-carnitine may improve ejection fraction in children with dilated cardiomyopathy and adults with ischemic cardiomyopathy. Details: Primary L-carnitine deficiency is a common cause of pediatric dilated cardiomyopathy. Additionally, patients with dilated cardiomyopathy of unknown etiology have been shown to have low cardiac levels of L-carnitine (59196,100351). Due to these findings, L-carnitine has been evaluated for the treatment of dilated cardiomyopathy in children and adults, but the small sizes of these studies and methodological limitations limit the reliability of the results. One small clinical study in children under 13 years of age with dilated cardiomyopathy shows that taking L-carnitine 50-100 mg/kg daily for 1 year in conjunction with standard care improves ejection fraction and reduces left atrial and ventricular diameters when compared with placebo and standard care (100351). The results of this study are limited by the small sample size, unclear etiology of dilated cardiomyopathy, and potential bias. Another small clinical study in children under 5 years of age with dilated cardiomyopathy and low serum levels of L-carnitine shows that taking L-carnitine 100 mg/kg daily for 3 months improves left ventricular ejection fraction (LVEF), cardiac output, and New York Heart Association (NYHA) classification when compared with baseline (59196). Further research is needed to clarify whether L-carnitine is beneficial for most children with dilated cardiomyopathy, or only those with carnitine deficiency. L-carnitine has also been evaluated in older adults. A meta-analysis of clinical studies in mostly older adults with dilated cardiomyopathy shows that addition of intravenous L-carnitine, alone or followed by oral L-carnitine, 1-6 grams daily to conventional therapy for a total of 10-28 days is associated with a 28% increased likelihood of overall efficacy, with improvements observed in both LVEF and cardiac output, when compared with conventional therapy alone (107405). The validity of these findings is limited by the heterogeneity of the included studies, potential publication bias, and unclear reporting. A small individual clinical study in older adults with ischemic cardiomyopathy shows that taking oral L-carnitine daily for 2 months improves LVEF when compared with baseline (58150). The validity of this finding is limited by the lack of a comparator group.
• Dry eye. Topical L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Evidence suggests that chronic use of eye drops containing benzalkonium chloride can cause tear film instability and lead to dry eye (90921). One small clinical trial in patients with glaucoma using eye drops containing benzalkonium chloride shows that using additional eye drops containing L-carnitine (1.017%), eledoisin (0.04%), taurine (0.49%), sodium hyaluronate (0.20 grams/100 mL), and vitamin E acetate (0.20 grams/100 mL) (Carnidrop Plus, Sigma-Tau) three times daily for 15 days reduces dry eye symptoms by approximately 50% when compared to baseline (90625). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Endometriosis. Although there has been interest in using oral L-carnitine for endometriosis, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Exercise-induced muscle damage. It is unclear if oral L-carnitine tartrate is beneficial for exercise recovery. Details: A small clinical study in healthy males and females participating in moderate physical activity at least 3 days weekly shows that taking a specific product (Carnipure, Lonza Consumer Health, Inc.) providing elemental L-carnitine 2 grams daily for 5 weeks improves perceived recovery and soreness as well as serum creatine kinase levels by 33% and 28%, respectively, when compared with placebo (107398).
• Exercise-induced muscle soreness. Small clinical studies suggest that oral L-carnitine may slightly reduce exercise-induced muscle soreness. Details: Evidence from mostly small clinical trials, when considered alone or combined via meta-analysis, shows that taking L-carnitine 1-3 grams daily for around 3 weeks modestly reduces exercise-induced muscle soreness, especially in the period of 24-48 hours after exercise. Benefits may last up to 96 hours post-exercise. Levels of creatinine kinase, lactate dehydrogenase, and myoglobin also appear to improve with L-carnitine supplementation, reflecting a reduction in muscle damage (58326,58709,59148,101567).
• Hepatic encephalopathy. Oral or intravenous L-carnitine may improve biochemical markers of disease severity in patients with hepatic encephalopathy, but L-carnitine does not seem to improve clinically important outcomes such as fatigue, quality of life, or overall disease severity. Details: A meta-analysis of nine studies in adults with hepatic encephalopathy shows that taking L-carnitine 1-6 grams daily orally or intravenously for up to 90 days increases albumin levels and decreases plasma levels of ammonia, bilirubin, aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine, but does not improve fatigue or quality of life, when compared with placebo (102122). A more recent clinical trial shows that taking L-carnitine 2 grams daily for 24 weeks modestly improves bilirubin levels and some measures of cognitive and liver health, but not quality of life, when compared with taking placebo (111876). Two of the clinical trials included in this analysis also show that taking L-carnitine 2 grams daily for 60-90 days significantly improves cognitive function when compared with placebo in adults with hepatic encephalopathy (58174,58204). Another small clinical trial in patients with advanced liver cirrhosis shows that L-carnitine improves psychometric response to the ammonia tolerance test, suggesting that L-carnitine might be useful in the prevention of hepatic encephalopathy (58872). L-carnitine has also been evaluated in combination with rifaximin. A small clinical study in patients with overt hepatic encephalopathy shows that taking oral L-carnitine 1500 mg in combination with rifaximin 1200 mg three times daily for 12 weeks has no effect on the modified portal systemic encephalopathy index when compared with rifaximin alone. L-carnitine improved blood ammonia levels at 4 weeks, but not at 8 or 12 weeks (107410).
• Hepatitis-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with hepatitis-related fatigue. Details: One small clinical trial in patients with hepatitis C who are receiving interferon-alpha treatment shows that taking L-carnitine 2 grams daily significantly reduces fatigue when compared with interferon-alpha alone. L-carnitine appears to reduce fatigue within the first 3 months of treatment, but not after 6 months (16104).
• Hepatitis B. Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with hepatitis B shows that taking a specific vitamin complex providing L-carnitine 2472 mg (Godex, Celltrion Pharm) in combination with entecavir 0.5 grams daily for 12 months normalizes alanine transaminase (ALT) levels in 95% and 100% of patients after 3 months and 12 months, respectively, compared to 59% and 86% of patients taking entecavir alone. However, the L-carnitine complex does not appear to improve aspartate transaminase (AST) levels or reduce hepatitis B virus titers (91724). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Hepatitis C. Small clinical studies suggest that oral L-carnitine may improve response to treatment and markers of liver function in patients with hepatitis C. Details: Two small clinical trials in patients with chronic hepatitis C show that taking L-carnitine 2 grams once or twice daily along with interferon-alpha and ribavirin for 12 months modestly improves response to treatment, increases hemoglobin and red blood cell counts, reduces aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and reduces steatosis when compared with interferon-alpha and ribavirin treatment alone (58405,59010).
• HIV/AIDS. Although there has been interest in using intravenous L-carnitine to increase CD4 counts in patients with HIV/AIDS, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Hyperthyroidism. It is unclear if oral L-carnitine is beneficial in patients with hyperthyroidism. Details: One small clinical trial in females with hyperthyroidism shows that taking L-carnitine 2-4 grams daily for 2-6 months seems to significantly improve symptoms associated with hyperthyroidism, such as palpitations, nervousness, tremors, and asthenia, when compared with placebo (8047).
• Hypertriglyceridemia. It is unclear if oral L-carnitine is beneficial in patients with hypertriglyceridemia. Details: Small clinical studies in patients with hypertriglyceridemia show that taking L-carnitine 1 gram daily for 12 weeks does not reduce triglyceride levels when compared with placebo (59028,59244).
• Hypothyroidism. It is unclear if oral L-carnitine is beneficial for improving fatigue in patients with hypothyroidism. Details: One small clinical trial in patients with secondary hypothyroidism shows that taking L-carnitine (Ildong Pharmaceutical Co.) 990 mg twice daily for 12 weeks in addition to adequate doses of levothyroxine does not reduce overall fatigue severity when compared with placebo. However, taking L-carnitine might improve physical and mental fatigue in patients with secondary hypothyroidism that are less than 50 years of age. L-carnitine might also improve mental fatigue in patients that underwent thyroidectomy for thyroid cancer (95069).
• Infertility. It is unclear if oral L-carnitine is beneficial for female infertility. Details: One uncontrolled clinical trial in females who had failed to conceive in previous in vitro fertilization (IVF) cycles shows that taking L-carnitine (L-CAR Basic Premium; AA Project Co. ltd.) 1000 mg daily for an average of 82 days does not improve the number of retrieved oocytes or fertilization rates when compared with previous IVF cycles. However, embryo quality at days 3 and 5 of insemination was improved, resulting in an increase in the rate of transferable embryos from 60% in previous cycles to 67%, morphologically good-quality embryos from around 46% to 54%, and blastocysts from around 11% to 21%. The most evidence of benefit was seen in those taking L-carnitine for the shortest time length of 7-44 days (96933).
• Intermittent claudication. Although there has been interest in using oral L-carnitine for intermittent claudication, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Liver disease. Small clinical studies suggest that oral L-carnitine may modestly improve some, but not all, lipid parameters in adults with liver disease. Details: A meta-analysis of six small, low-quality clinical trials in patients with hepatitis C, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) shows that taking L-carnitine moderately reduces total cholesterol and slightly reduces triglyceride levels, but does not improve low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol levels, when compared with control. Studies evaluating L-carnitine doses of 2 grams daily or less and study durations of 24 months or longer showed the largest effect on lipid levels (104178). Another meta-analysis of preliminary clinical research in patients with hepatitis B or C, hepatic encephalopathy, NASH, or NAFLD shows that taking L-carnitine modestly reduces levels if aspartate aminotransferase (AST) and alanine aminotransferase (AST) when compared with taking placebo or no L-carnitine. Some of the studies included in this analysis used acetyl-L-carnitine. However, a meta-analysis of two studies investigating the effect of carnitine orotate shows that taking this compound increases the proportion of patients with normal ALT levels by 4.6 fold (111871).
• Liver transplant. It is unclear if oral L-carnitine is beneficial in patients awaiting a liver transplant. Details: One small clinical trial shows that taking L-carnitine 500 mg three times daily while awaiting a liver transplant does not reduce the incidence of primary graft dysfunction (PGD) or non-function (PNF) when compared with placebo. However, survival one month after surgery was 97% in those taking L-carnitine, compared with 74% in those taking placebo (101562). This study may have been inadequately powered to detect a difference in the incidences of PGD and PNF between groups.
• Low birth weight. It is unclear if oral or intravenous L-carnitine is effective for increasing body weight in preterm infants. Several small clinical studies show conflicting results. Details: Several very small clinical trials in preterm infants receiving total parenteral nutrition show that administering L-carnitine orally at a dose of 13-60 mcmol/kg or intravenously at a dose of 10 mg/kg or 50-100 mcmol/kg daily can improve fat utilization and weight gain when compared with control (3633,3634,3635,3636,3637,58902,59097). However, other small clinical studies show that supplementation with L-carnitine does not significantly increase body weight in preterm infants (58190,58800,59161). The reasons for the discrepant findings are unclear, but due to small study size, some of the studies may have been underpowered to detect significant differences between groups.
• Lyme disease. Although there has been interest in using oral L-carnitine for Lyme disease, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Metabolic syndrome. It is unclear if oral or intravenous L-carnitine is beneficial in patients with metabolic syndrome. Details: One very small clinical trial in patients with metabolic syndrome undergoing 2 days of moderate calorie restriction followed by a 5-day modified fasting period shows that intravenous L-carnitine 2 grams twice daily for 7 days increases weight loss by 1.4 kg and decreases waist circumference by 3.3 cm when compared with intravenous saline. Perceived hunger scores, physical fatigue, and insulin levels were also improved. However, there were no effects on blood pressure (90634). Other clinical research in patients with metabolic syndrome and a total carotid plaque volume of at least 50 mm³ shows that taking L-carnitine 2 grams daily for 6 months does not affect the progression of carotid plaque volume when compared with taking placebo. Also, taking L-carnitine increased the progression of carotid plaque stenosis by 9.3%, as well as levels of low-density lipoprotein (LDL) cholesterol, in this population (111879).
• Migraine headache. It is unclear if oral L-carnitine is beneficial in patients with migraine headaches. Details: One small clinical trial in patients with migraines shows that taking L-carnitine 500 mg daily, with or without magnesium oxide, for 12 weeks does not significantly reduce migraine frequency or severity when compared with a control (59030). However, another small preliminary clinical trial in children with episodic migraines shows that taking L-carnitine 25 mg per kg twice daily for 12 weeks prophylactically is as effective as taking propranolol 1 mg/kg once daily for reducing the frequency, severity, and duration of migraine headaches (111870). These studies were small and may have been underpowered to detect differences between groups.
• Muscle cramps. It is unclear if oral L-carnitine is beneficial in patients with muscle cramps. Details: One small, uncontrolled clinical trial in adults with type 2 diabetes shows that taking L-carnitine 300 mg twice daily for 4 months decreases the monthly frequency of muscle cramps from around 4 cramps per month at baseline to around 1 cramp per month after treatment. When compared with baseline, pain was also reduced by about 1 point on a 5-point scale (96922). However, the lack of a placebo control group limits the validity of these findings.
• Multiple sclerosis-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with multiple sclerosis-related fatigue. Details: Some patients with multiple sclerosis have low blood levels of L-carnitine. Additionally, immunosuppressive therapy for multiple sclerosis can cause fatigue. One small, open-label clinical trial in patients with multiple sclerosis receiving immunosuppressive therapy and with low L-carnitine levels shows that taking L-carnitine 3-6 grams daily decreases some measures of fatigue when compared with no treatment (16107).
• Myocardial infarction (MI). It is unclear if oral or intravenous L-carnitine is beneficial in patients who have experienced an MI. Details: Some clinical research shows that taking L-carnitine orally or intravenously after MI reduces premature ventricular beats (58172,59044), improves myocardial viability (59248) and left ventricular function (3628), and reduces mortality (3627,3629,59037). However, other studies show no change in left ventricular functioning (58148) or mortality after taking L-carnitine (3628,58225,90630). The reasons for these discrepant findings are unclear, but may be due to differences in the dosing regimens and length of follow-up. Oral L-carnitine doses have ranged from 2-4 grams daily for up to 12 months (3627,3629,59248). Intravenous L-carnitine has been dosed at 5 grams within the first 36 hours after an MI followed by 3 grams twice daily on days 3-7 (58172), 100 mg/kg every 12 hours for 36 hours (59044), or 9 grams daily for 5 days followed by oral L-carnitine 6 grams daily for 12 months (3628).
• Narcolepsy. It is unclear if oral L-carnitine is beneficial in patients with narcolepsy. Details: One small clinical trial in patients with narcolepsy shows that taking L-carnitine 340 mg in the morning and 170 mg in the evening for 8 weeks reduces dozing off time during the day by about 9 minutes when compared with placebo. However, the number of naps needed, quality of life, and sleepiness are not affected (90624).
• Neonatal apnea. It is unclear if intravenous L-carnitine is beneficial for preventing neonatal apnea in premature infants. Details: One small clinical trial in premature infants shows that adding L-carnitine 30 mg/kg daily to total parenteral nutrition or oral feeds does not affect ventilator requirements or reduce the incidence of apnea when compared with placebo (58163).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral L-carnitine is beneficial in children and adults with NAFLD. Details: One small clinical study in adults with NAFLD shows that taking L-carnitine 600 mg daily for 3 months improves markers of liver function when compared with baseline. No improvements in liver function markers were reported in patients in the control group; however, no statistical comparisons were conducted between groups (58808). A small clinical study in children aged 5-15 years with NAFLD receiving vitamin E shows that taking L-carnitine 25 mg/kg twice daily (maximum of 500 mg twice daily) for 3 months has no effect on aminotransferase concentrations or sonographic grades of fatty liver when compared with placebo (107401).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral L-carnitine is beneficial in patients with NASH. Details: One small clinical trial in patients with NASH shows that taking L-carnitine 1 gram after breakfast and 1 gram after dinner daily along with following a specific diet improves markers of liver function when compared with diet alone (58715). Another small clinical trial in patients with obesity and nonalcoholic steatohepatitis taking simvastatin 20 mg daily and following a hypocaloric diet shows that taking L-carnitine 10 mL twice daily for 90 days modestly reduces BMI, and improves liver health, lipid, and glycemic indices, when compared with taking a product described as essential phospholipids (111893).
• Obesity. Oral L-carnitine seems to have a small effect on weight loss in overweight or obese individuals when taken for up to 6 months, but some conflicting results exist. Doses of 2 grams daily seem to offer the most benefit. Details: Meta-analyses of clinical trials show that taking L-carnitine 250 mg to 4 grams daily reduces weight and body mass index (BMI) by a small amount when compared with a control group not taking L-carnitine (95074,101563,101564). Subgroup analyses show that L-carnitine only reduces BMI and weight in overweight or obese patients. Taking L-carnitine did not affect weight or BMI in patients with a BMI of up to 25 kg/m2 or in patients undergoing hemodialysis (101563,101564). Another subgroup analysis shows that the largest benefit occurs at a dose of 2 grams daily (101564). In patients with obesity and nonalcoholic steatohepatitis taking simvastatin 20 mg daily and following a hypocaloric diet, one clinical trial shows that taking L-carnitine 10 mL twice daily for 90 days modestly reduces BMI, and improves liver health, lipid, and glycemic indices, when compared with taking a product described as essential phospholipids (111893). However, conflicting results exist. One subgroup analysis in overweight or obese individuals shows that there is no effect on BMI when L-carnitine is taken for 24 weeks or more (101563). One meta-analysis of two small clinical trials in patients with overweight or obesity shows that taking L-carnitine is no more effective than lifestyle modification for reducing body weight (111866). Also, some clinical research shows that taking L-carnitine does not reduce body weight in obese females. Doses used in these studies include L-carnitine 1 gram daily for 12 weeks or 2 grams twice daily for 8 weeks along with exercise (58151,111872). The effect of L-carnitine on cardiovascular risk has also been examined in patients with obesity. One small clinical trial shows that taking L-carnitine 1 gram daily for 12 weeks modestly reduces the lipid accumulation index, based on waist circumference and blood triglyceride levels, when compared with taking placebo. However, there was no effect on other cardiovascular risk indices based on ratios of triglycerides, high-density lipoprotein (HDL) cholesterol, and/or low-density lipoprotein (LDL) cholesterol levels (111872). L-carnitine has also been evaluated in combination with weight loss medications. Clinical research shows that taking L-carnitine 2 grams daily along with orlistat 360 mg daily or sibutramine 10 mg daily for 1 year decreases body weight and BMI when compared with orlistat or sibutramine alone in obese adults with type 2 diabetes (58778,58830,58882).
• Osteoarthritis. It is unclear if oral L-carnitine is beneficial in patients with knee osteoarthritis. Details: A small clinical study in females with knee osteoarthritis and overweight or obesity who are on a low-calorie diet shows that taking L-carnitine 1 gram daily for 12 weeks does not improve pain, stiffness, or physical function when compared with placebo (107403).
• Pemphigus. Although there has been interest in using oral L-carnitine for glucocorticoid-induced muscle wasting in patients with pemphigus, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Peripheral arterial disease (PAD). It is unclear if oral L-carnitine is beneficial in patients with PAD. Details: One small clinical trial in patients with PAD shows that taking L-carnitine 2 grams twice daily for 3 weeks may improve walking distances in people with PAD (3631). However, another small clinical trial in patients with PAD or coronary heart disease shows that taking L-carnitine 2 grams two hours before exercise does not improve endurance (58196). Also, adding L-carnitine 1 gram twice daily to cilostazol therapy for 180 days does not appear to confer additional benefit in this patient population (59023).
• Polycystic ovary syndrome (PCOS). It is unclear if oral L-carnitine is beneficial for improving pregnancy rates or cardiovascular risk in people with PCOS. The effect of L-carnitine on body composition has promising results. Details: Clinical research shows that adding L-carnitine 3 grams daily for 3 months to standard clomiphene plus metformin therapy improves menstrual regularity by 20%, ovulation rate by 24%, and pregnancy rate by 21% when compared with placebo (102123). Preliminary clinical research in patients with PCOS who are resistant to both clomiphene and human chorionic gonadotropin (HCG) shows that taking L-carnitine 2 grams twice daily from day 3 of clomiphene treatment until HCG injection results in the presence of a dominant follicle in 64% of cycles and pregnancy in 20% of cycles (96936). However, L-carnitine may not be beneficial in combination with assisted reproductive technology (ART), including in vitro fertilization and intracytoplasmic sperm injection. A small clinical study in patients with PCOS receiving ART in combination with a gonadotropin-releasing hormone antagonist protocol shows that adding L-carnitine 3000 mg daily during the induction of ovulation (from the second day of the cycle until the day of oocyte triggering) does not improve pregnancy rates in frozen-thawed embryo transfer cycles when compared with control (107409). The effect of L-carnitine has also been examined on anthropometric and cardiovascular risk indices in patients with PCOS. One small clinical study shows that taking L-carnitine 250 mg daily for 12 weeks reduces body weight by 2.8 kg, body mass index (BMI) by 1.2 kg/m2, waist circumference by 1.7 cm, and hip circumference by 2.2 cm when compared with placebo (96935). A meta-analysis of this and other small studies also shows that L-carnitine modestly reduces BMI when compared with placebo in patients with PCOS (111873). Although several studies also show improvements in markers of glycemic control and insulin sensitivity, most research does not support beneficial effects on lipid levels, cardiovascular risk, or liver fat content (96935,107402,107404).
• Rett syndrome. It is unclear if oral L-carnitine is beneficial in patients with Rett syndrome. Details: Two small clinical studies in children with Rett syndrome show that taking L-carnitine 100 mg/kg daily in two or three divided doses for up to 6 months modestly improves well-being, motor skills, sleep efficiency, and communication skills when compared with control or placebo (1433,58161).
• Sarcopenia. Oral L-carnitine may be beneficial for preventing sarcopenia in adults over 75 years of age, but not in healthy older females. Details: One small clinical trial in healthy, active, older females aged 65-70 years shows that taking L-carnitine, as L-carnitine-l-tartrate 1500 mg, daily for 24 weeks does not improve muscle strength or muscle mass when compared with placebo (96930). An additional preliminary clinical trial in females aged 60-75 years taking part in a twice weekly resistance exercise program shows that taking L-carnitine tartrate 1 gram daily with L-leucine 3 grams daily for 24 weeks does not improve muscle strength or volume when compared with taking L-leucine 4 grams daily or no supplementation (111880). These studies were small and may have been underpowered to detect differences. In contrast, in weaker adults 75 years of age and older, taking L-carnitine 2-4 grams daily for 1-6 months increases muscle mass by approximately 2-4 kg when compared with placebo (16109,16111).
• Sepsis. Small clinical studies suggest that intravenous L-carnitine may not reduce mortality in patients with sepsis, although patients with more severe sepsis may see some benefit. Details: Meta-analyses of generally low-quality small clinical trials in patients with sepsis shows that intravenous administration of L-carnitine, 2-6 grams as a bolus followed by a 4-12 gram infusion, does not reduce the risk of 28-day or 1-year mortality when compared with placebo (104180,111868). However, in a subgroup analysis of patients with more severe sepsis, classified as those with a sequential organ failure assessment score (SOFA) of greater than 12, the risk of 1-year mortality was reduced by 32% when compared with placebo (104180).
• Spinal muscular atrophy. Although there has been interest in using oral L-carnitine for spinal muscular atrophy, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Theophylline-induced cardiac toxicity. It is unclear if intravenous L-carnitine is beneficial in patients with theophylline-induced cardiac toxicity. Details: One small clinical trial shows that intravenous administration of L-carnitine 100 mg/kg over 30-60 minutes followed by 50 mg/kg every 8 hours along with intravenous propranolol within 24 hours of theophylline intoxication improves symptoms associated with theophylline-induced cardiac toxicity when given along with standard treatment. This combination led to greater improvements than either agent used alone. These included improvements in serum theophylline levels, heart rate, arrhythmia, mean arterial pressure, and duration of hospital stay. When L-carnitine was used without propranolol, only respiratory rate and theophylline levels over 24 hours were improved to a greater extent than with standard treatment alone (101566).
• Toxin-induced liver damage. Small clinical studies have evaluated oral and intravenous L-carnitine for the management of liver damage caused by different classes of drugs, including antimycobacterial antibiotics and asparaginase-based agents, with promising results. Details: The antimycobacterial antibiotics used to treat tuberculosis, including isoniazid, rifampicin, and pyrazinamide, have been associated with hepatotoxicity (90922). Clinical research shows that taking L-carnitine 2 grams in two divided doses daily for 4 weeks along with a standard treatment regimen for tuberculosis reduces the percentage of treatment-naïve patients with drug-induced hepatotoxicity by almost half when compared with placebo (26499). The asparaginase-based medications have also been associated with hepatotoxicity. Two case series of children with hyperbilirubinemia caused by treatment with L-asparaginase or pegaspargase show that administering intravenous L-carnitine 50-100 mg/kg daily improves bilirubin levels (100353,100354). One case series also suggests that taking oral L-carnitine 50-100 mg/kg daily can help to prevent hyperbilirubinemia in patients with a history of asparaginase-induced hepatotoxicity (100353).
• Traumatic brain injury (TBI). Although there has been interest in using oral L-carnitine for TBI, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Urinary tract infections (UTIs). It is unclear if oral L-carnitine is beneficial in children with UTIs. Details: One small clinical trial in children 6 months to 10 years of age shows that taking L-carnitine 50 mg/kg daily as a syrup along with antibiotics for 7 days prevents renal scarring associated with acute pyelonephritis. Kidney damage was resolved in 50% of children taking L-carnitine, compared with 13% of children taking placebo. There were no differences in urine cultures between groups (101568).
• Venous leg ulcers. Although there has been interest in using oral L-carnitine for venous leg ulcers, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose. More evidence is needed to rate L-carnitine for these uses.

(Read more about L-CARNITINE)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Intranasal resveratrol seems to be beneficial for reducing allergic rhinitis symptoms in adults and children. Details: Some clinical research shows that intranasal resveratrol with carboxymethyl-beta-glucan can improve symptoms of allergic rhinitis (91332,97339). One clinical study in adults with allergic rhinitis shows that using an intranasal spray containing resveratrol 0.1% three times daily for 4 weeks reduces nasal symptoms and improves quality of life scores when compared with placebo (97339). A study in children aged 4-17 years with pollen-induced allergic rhinitis shows that using an intranasal spray containing resveratrol 0.05% three times daily for 2 months improves itching, sneezing, runny nose, and nasal obstruction and reduces use of rescue medication when compared with placebo (91332).
• Obesity. Oral resveratrol seems to be beneficial for weight loss in individuals with overweight or obesity. However, it is unlikely to be beneficial for improving most metabolic parameters in this population. Details: A meta-analysis of 28 clinical trials shows that taking resveratrol decreases body weight by 0.5 kg, body mass index (BMI) by 0.17 kg/m2, and waist circumference by 0.8 cm when compared with placebo or no intervention. This analysis included studies of individuals with normal weight, overweight, and obesity, with or without type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, or other chronic conditions. A subgroup analysis suggests that individuals with obesity have a greater response to resveratrol. In these individuals, taking resveratrol 8-3000 mg daily resulted in an average weight reduction of 1.15 kg and a BMI reduction of 0.3 kg/m2 when compared with placebo. The greatest impact on body weight and BMI occurred with resveratrol doses of no more than 500 mg daily and treatment durations of at least 3 months (100696). One clinical trial also shows that taking resveratrol 150 mg daily for 6 months reduces glycated hemoglobin (HbA1c) by a small amount when compared with placebo in individuals with overweight or obesity but has no effect on insulin sensitivity, fat mass, or levels of fasting blood glucose, lipids, or liver enzymes (105183). Also, meta-analyses of clinical research show that resveratrol is unlikely to be beneficial for improving blood pressure or blood lipids when compared with placebo in individuals with overweight or obesity (102513,105181).

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Oral resveratrol does not seem to be beneficial for CVD prevention. Details: Population research suggests that a higher dietary intake of resveratrol is not associated with a reduced risk of CVD when compared with a lower dietary intake (91334). Also, a meta-analysis of clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides in patients at high risk for CVD (91333). While one preliminary clinical study shows that taking resveratrol 10 mg daily for 3 months improves left ventricular function by about 1% and endothelial function when compared to baseline in patients with a history of myocardial infarction and coronary artery disease, the improvements are very small and blood pressure and markers of inflammation do not appear to be improved (91330).
• Hypercholesterolemia. Oral resveratrol does not seem to be beneficial for hypercholesterolemia. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving blood lipids when compared with placebo in patients with hypercholesterolemia. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), angina, and dyslipidemia (105181). Although there was a small reduction in total cholesterol levels of approximately 7 mg/dL, resveratrol did not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (105181). Also, an analysis of results from clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides in patients at high risk for cardiovascular disease (91333). Also, clinical research in healthy humans shows that taking resveratrol 500 mg orally daily for 30 days increases levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B (112944). Another meta-analysis identified more promising results; however, any effect on blood lipids may not be considered clinically significant. This meta-analysis included 17 clinical studies enrolling 968 participants with dyslipidemia, type 2 diabetes, coronary artery disease, overweight or obesity, or stroke. Resveratrol reduced total cholesterol by approximately 10 mg/dL, LDL by approximately 6 mg/dL, and triglycerides by approximately 9 mg/dL, but did not improve HDL, when compared with placebo. However, most of the included studies were small and utilized heterogenous dosing regimens, with doses ranging from 10-3000 mg daily for 4-48 weeks (110020).
• Metabolic syndrome. Oral resveratrol does not seem to be beneficial for metabolic syndrome. Details: A meta-analysis of clinical research shows that taking resveratrol does not improve blood pressure when compared with placebo in patients with metabolic syndrome or related disorders (102513). A similar meta-analysis shows that taking resveratrol does not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or liver enzymes. There was a small reduction in total cholesterol levels of approximately 7 mg/dL (105181). However, only 3-4 of the papers included in these meta-analyses, which included 28-31 publications, evaluated patients with metabolic syndrome. The remainder included patients with related conditions, such as overweight/obesity, type 2 diabetes, or nonalcoholic fatty liver disease (NAFLD). The mainly small or preliminary clinical studies that did evaluate patients with metabolic syndrome all show that taking resveratrol 100-1000 mg daily for 12-16 weeks does not improve blood pressure, glucose control, or plasma lipids (91331,95828,102513,105181). However, one preliminary clinical trial shows that taking resveratrol 500 mg three times daily for 3 months reduces body weight by about 4 kg, body mass index (BMI) by 1.3 kg/m2, fat mass by 2.4 kg, and waist circumference by 4 cm when compared to baseline (91331). The validity of these findings is limited by the lack of a comparator group. Also, a moderate-sized clinical trial of adults with metabolic syndrome shows that taking resveratrol 300 mg and delta-tocotrienols 500 mg daily for 24 weeks improves body weight, waist circumference, blood pressure, fasting blood glucose, triglycerides, total and HDL cholesterol, and markers of inflammation and oxidative stress when compared with placebo (112144). It is unclear if these effects are due to resveratrol, delta-tocotrienols, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Oral resveratrol does not seem to be beneficial for most metabolic symptoms of NAFLD. It is unclear if oral resveratrol is beneficial for improving steatosis. Details: Although some individual studies disagree, meta-analyses reviewing 4-6 preliminary clinical studies show that taking resveratrol does not affect liver enzyme levels, insulin resistance, blood pressure, blood lipids, body mass index (BMI), or abdominal size when compared with placebo in patients with NAFLD (95826,99048,105184). Most trials have studied doses of 300-3000 mg daily for 2-3 months; one study used resveratrol 500 mg 3 times daily for 6 months (95826,98911,99048,105184). However, one meta-analysis shows that taking resveratrol might have a small effect on levels of the inflammatory mediators C-reactive protein and tumor necrosis factor (TNF)-alpha (105184). It is not clear if resveratrol might reduce steatosis in patients with NAFLD. One preliminary clinical study shows that taking resveratrol 3000 mg daily in two divided doses for 8 weeks does not improve steatosis when compared to baseline in males with NAFLD (91327). However, another preliminary clinical study in adults with NAFLD shows that taking resveratrol 500 mg daily for 3 months, while following an energy-balanced diet and exercising, improves steatosis, but not fibrosis, insulin resistance, lipid levels, or body composition, when compared with lifestyle modifications alone (91328). The difference in these findings might be due to small study sizes, the duration of therapy, or the gender of the included patients.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical resveratrol is beneficial for acne. Details: Preliminary clinical research shows that applying a gel containing trans-resveratrol 1 mcg per gram to facial skin for 60 days reduces the severity of acne by about 54%, compared to only 6% for control gel (71064).
• Age-related cognitive decline. It is unclear if oral resveratrol is beneficial for age-related cognitive decline. Details: One small clinical study shows that taking resveratrol 75 mg twice daily for 14 weeks modestly improves cognitive performance and memory after menopause, but not executive function or learning, when compared with placebo (95827). Another small clinical study in healthy, older adults shows that taking resveratrol 200 mg daily for 26 weeks improves memory retention, but not delayed recall or word recognition, when compared with placebo. In this study, resveratrol capsules were formulated to also contain 320 mg of quercetin to enhance the absorption of resveratrol (102511). It is unclear if resveratrol alone would result in similar effects. Despite these positive results, conflicting research exists. A small clinical study in sedentary, overweight, elderly adults shows that taking resveratrol 300 mg daily for 90 days does not improve measures of cognitive function such as psychomotor speed, attention, executive function, learning, or memory when compared with placebo. Taking a higher dose of 1000 mg daily for 90 days modestly improves psychomotor speed, but no other cognitive measures, in these patients (98907). Another small clinical study in healthy elderly adults shows that taking resveratrol 200 mg daily for 26 weeks does not improve verbal memory when compared with placebo (98909).
• Aging skin. Although there has been interest in using oral resveratrol for aging skin, there is insufficient reliable information about the clinical effects of resveratrol for this purpose.
• Beta-thalassemia. It is unclear if oral resveratrol is beneficial for beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia intermedia shows that taking micronized trans-resveratrol (Xian Tianxingjian Natural Bio-Products CO., LTD) 2000 mg with piperine (Bioprex Co.) 40 mg, with or without hydroxyurea 8-15 mg/kg, daily for 6 months does not improve hemoglobin levels or affect the need for blood transfusion when compared with taking placebo with or without hydroxyurea (98908).
• Cancer. It is unclear if dietary resveratrol is beneficial for cancer prevention. Details: Population research has found that a higher dietary intake of resveratrol is not associated with a reduced risk of cancer when compared to lower dietary intake (91334).
• Chronic obstructive pulmonary disease (COPD). Oral resveratrol 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 resveratrol 10 mg, vitamin C 180 mg, zinc 15 mg, and flavonoids 160 mg daily for 20 days followed by 10 days without supplementation, repeated for three cycles, modestly reduces symptoms of cough and sputum production in patients with mild-to-moderate COPD when compared with control (71130). It is not clear if these effects are due to resveratrol, the other ingredients, or the combination.
• Cognitive function. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy young adults shows that taking a specific supplement (Transmax by BiotiviaTM) containing trans-resveratrol 500 mg and piperine 10 mg daily for 28 days does not improve most measures of cognitive performance when compared with placebo (95834).
• Cognitive impairment. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in a small number of patients with mild cognitive impairment shows that taking resveratrol 200 mg and quercetin 350 mg daily for 26 weeks does not improve learning and memory performance when compared with placebo (102512). However, given the small sample size, it is possible this study was inadequately powered to detect significant changes in these cognitive measures.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral resveratrol is beneficial for COVID-19. Details: A small clinical trial in outpatients with COVID-19 shows that taking resveratrol (Vita-Age) 1 gram four times daily, for 7-15 days based on symptom duration, does not reduce the rate of hospitalization, emergency room visits, or pneumonia when compared with placebo. All patients also received a single dose of Vitamin D3 (109164). This study may have been inadequately powered to detect differences between groups.
• Diabetes. Some research shows that oral resveratrol is beneficial for improving glycemic indices in patients with type 2 diabetes. However, more research is needed to determine the most effective dose or the patient population most likely to benefit. Details: Although results from individual clinical studies have been mixed (91329,95825,95832,100695,109165,109167,109170), meta-analyses of clinical research show that resveratrol modestly reduces blood glucose and glycated hemoglobin (HbA1c) levels in patients with diabetes. Studies lasted 4-24 weeks and many included patients treated with antidiabetes medications, including metformin. However, these meta-analyses have yielded differing findings regarding effective doses (91329,109165,109167,109170). One meta-analysis of clinical research in individuals aged 45 years and older shows that doses of 250-1000 mg daily modestly reduce levels of fasting blood glucose, insulin, and HbA1c, as well as insulin resistance, when compared with placebo. Doses of up to 250 mg daily are generally ineffective, and only one study used doses greater than 1000 mg daily. Although sub-analyses suggest that these benefits may be limited to individuals aged 45-59 years, the number of studies in older individuals is small and findings are unclear (109165). A second meta-analysis in adults with type 2 diabetes suggests that resveratrol doses of at least 500 mg daily were necessary for reducing levels of fasting blood glucose and insulin, as well as insulin resistance (109167). A third meta-analysis, which also included Chinese language publications, shows that doses of resveratrol of at least 1000 mg daily are needed for improved glycemic control (109170). Some studies have used a specific resveratrol product (Biotivia Bioceuticals, International SrL) (95825). Although the reasons for discrepancies between individual clinical trials are not clear, it is possible that conflicting results are related to baseline blood glucose control. Resveratrol has shown benefit in patients with diabetes that is not well-controlled at baseline (HbA1c of 8% or higher) (91329), while results are mixed in patients with diabetes that is at least moderately well-controlled prior to supplementation (HbA1c of 7% or lower) (95825,100695). It is also possible that the differences may relate to the technique used to measure outcomes. For instance, resveratrol appears to improve insulin resistance when measured by the Stumvoll insulin sensitivity index, but not by the gold-standard hyperinsulinemic-euglycemic clamp technique (95832). Resveratrol has also been evaluated for improving blood pressure, blood lipid, and liver transaminase levels in patients with type 2 diabetes. Meta-analyses of clinical trials show that resveratrol has a small, but likely clinically insignificant, effect on systolic blood pressure when compared with placebo. Two meta-analyses show similar findings for diastolic blood pressure; however, some research suggests that any benefits are limited to doses of at least 500 mg daily (102513,109167,109170). Most meta-analyses of clinical research show that resveratrol does not improve blood lipid levels (105181,109167,109170) or liver transaminase levels (105181) when compared with placebo. Other clinical research in patients with overweight and type 2 diabetes shows that taking resveratrol 1000 mg daily for 8 weeks does not affect hepatic steatosis or cardiovascular risk indices when compared with placebo (109169).
• Diabetic nephropathy. It is unclear if oral resveratrol is beneficial for diabetic nephropathy. Details: Preliminary clinical research in patients with diabetic nephropathy shows that taking resveratrol 500 mg plus losartan 12.5 mg daily for 90 days can reduce urinary albumin-to-creatinine ratios, but not serum creatinine levels or glomerular filtration rates, when compared with taking placebo and losartan. When compared to baseline, the urinary albumin-to-creatinine ratio decreased by 46 mg/gram with resveratrol and increased by 25 mg/gram with placebo (100695).
• Hypertension. It is unclear if oral resveratrol is beneficial for lowering blood pressure. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving systolic or diastolic blood pressure when compared with placebo in patients with hypertension. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), stroke, and dyslipidemia (102513). More research is needed in patients with hypertension.
• Migraine headache. It is unclear if oral resveratrol is beneficial for treating migraine headache. Details: A small clinical crossover study in patients with hormonal migraine headaches shows that taking resveratrol (Veri-te Resveratrol, Evolva SA) 75 mg twice daily for 3 months does not affect headache frequency, severity, or disability when compared with placebo (109166). However, this study did not include a wash-out period between treatments, introducing the potential for carry-over effects.
• Mitochondrial myopathies. It is unclear if oral resveratrol is beneficial for increasing exercise tolerance in patients with mitochondrial myopathies. Details: A very small clinical trial in adults with mitochondrial myopathies shows that taking resveratrol (Veri-te resveratrol) 500 mg twice daily for 8 weeks does not improve exercise capacity when compared with placebo (109162). This study may have been inadequately powered to detect differences between groups.
• Osteoarthritis. It is unclear if oral resveratrol is beneficial for osteoarthritis. Details: A small clinical study in patients with mild or moderate knee osteoarthritis receiving physical therapy and meloxicam 15 mg daily shows that adding resveratrol 500 mg daily for 90 days improves pain, function, and stiffness when compared with adding placebo (98910).
• Osteopenia. It is unclear if oral resveratrol is beneficial for improving bone mineral density (BMD). Details: A meta-analysis of clinical research shows that taking resveratrol at doses of up to 1500 mg daily for 1-12 months does not increase BMD or alter bone biomarkers when compared with placebo (109163). The studies in this meta-analysis included various populations, such as postmenopausal or overweight individuals, or patients with type 2 diabetes or metabolic syndrome. However, a clinical study in healthy, postmenopausal females shows that taking fermented soy 200 mg, containing resveratrol 25 mg and equol 10mg, orally daily for 12 months increases whole-body BMD when compared with placebo. Levels of markers of bone formation, including osteocalcin and bone-specific alkaline phosphatase, are increased, and the level of deoxypyridinoline, a marker of bone resorption, is decreased (112942).
• Periodontitis. It is unclear if oral resveratrol is beneficial for periodontitis. Details: A small clinical study in individuals with chronic moderate-to-severe periodontitis who recently received non-surgical treatment for periodontitis shows that taking resveratrol 480 mg daily for 4 weeks improves plaque index when compared with placebo, but resveratrol does not seem to improve other markers of periodontitis, including pocket depth, bleeding index, clinical attachment loss, or salivary markers of inflammation (112135). The study may have been inadequately powered and too short in duration to detect a difference between the groups.
• Peritoneal dialysis. It is unclear if oral resveratrol can improve outcomes with peritoneal dialysis. Details: One clinical study shows that taking trans-resveratrol 150 mg or 450 mg daily for 12 weeks increases ultrafiltration rate and volume when compared with placebo in patients on peritoneal dialysis. The effect appears to be dose-dependent (95830).
• Polycystic ovary syndrome (PCOS). It is unclear if oral resveratrol is beneficial for PCOS. Details: Clinical research in patients with PCOS shows that taking resveratrol 1000 mg daily for 3 months results in a regular menstruation cycle length in 77% of individuals, compared with 52% of those taking placebo. The occurrence of hair loss was reduced by about 50%; however, there was no effect on hormone, metabolic, or lipid profiles. There was also a small increase in fat mass and decrease in fat-free mass, although the clinical relevance of these changes is unclear (109131). A small clinical trial in adults with PCOS shows that taking micronized trans-resveratrol (RevGenetics) 1500 mg daily for 3 months decreases levels of testosterone, but does not improve weight, lipid levels, insulin sensitivity, acne, or hirsutism, when compared with placebo (95823). A meta-analysis of 4 controlled trials of resveratrol, taken orally in doses of 800-1500 mg daily for 40 days to 3 months, shows reductions in levels of testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate when compared with placebo, but no effect on follicle stimulating hormone, prolactin, thyroid stimulating hormone, C-reactive protein, insulin, sex hormone binding globulin, lipids, acne, or pregnancy rates (112943).
• Rheumatoid arthritis (RA). It is unclear if oral resveratrol is beneficial for RA. Details: A small clinical study shows that adding resveratrol 1 gram orally once daily as adjunct therapy to antirheumatic drugs for 2 months reduces the number of tender and swollen joints, as well as biomarkers of inflammation. It is not known whether resveratrol reduces joint damage when assessed using conventional radiography. Also, the most effective combination of resveratrol and antirheumatic drug is not known, since the patients in this study were taking different antirheumatic drugs at variable doses (95706).
• Sciatica. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with sciatica secondary to a herniated disk shows that taking a combination of resveratrol 50 mg with alpha-lipoic acid, acetyl-L-carnitine, 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). It is unclear if the effects are due to resveratrol, other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral resveratrol is beneficial for ulcerative colitis. Details: Preliminary clinical research shows that taking trans-resveratrol (Sumabe Company) 500 mg daily for 6 weeks reduces subjective measures of disease activity and improves quality of life measures when compared with placebo in patients with mild to moderate active ulcerative colitis (95831). More evidence is needed to rate resveratrol 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. L-carnitine has been safely used in clinical trials lasting up to 12 months (1947,3620,3621,3623,3624,3625,3626,3627,3628,3629) (3630,3639,4949,8047,9790,12352,16104,16105,16106,16107) (16109,16110,23437,26496,26499,58150,58156,58161,58169,58182) (58189,58204,58207,58209,58213,58294,58523,58554,58556,58647) (58679,58715,58778,58793,58830,58831,58882,59023,59029,59043) (90624,90633,104177,111872,111876,111883,111884,111891,111898). ...when used parenterally as an FDA-approved prescription medicine. Avoid using D-carnitine and DL-carnitine. These forms of carnitine can act as competitive inhibitors of L-carnitine and may cause symptoms of L-carnitine deficiency (1946).

CHILDREN: POSSIBLY SAFE
when used orally or intravenously and appropriately. L-carnitine has been safely used orally in children for up to 6 months (1433,3622,58166,58502,58981,59188,111887,111900). It has also been safely used orally and intravenously in preterm infants (3633,3634,3635,3636,3637,58163,58190,58800,58902,59097)(59161).

PREGNANCY:
Insufficient reliable information available; avoid using.

LACTATION: POSSIBLY SAFE
when used orally. Supplemental doses of L-carnitine have been given to infants in breast milk and formula with no reported adverse effects. The effects of large doses used while nursing are unknown, but L-carnitine is secreted in the breast milk (3616).

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LIKELY SAFE ...when used in amounts found in foods (2030).

POSSIBLY SAFE ...when taken orally in doses of up to 1500 mg daily for up to 3 months (71066,71097,91328,91331,95825,95833,98910,100695,105183,109163,109167). Higher doses of 2000-3000 mg daily have been well tolerated when taken for 2-6 months, but are more likely to cause gastrointestinal side effects (91327,98908). ...when used topically for up to 30 days (71064). ...when used as an intranasal spray for up to 4 weeks (97339).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used as an intranasal spray for up to 2 months in children 4 years of age and older (91332). There is insufficient reliable information available about the safety of resveratrol when used by mouth in larger amounts as medicine.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods (2030). Resveratrol is found in grape skins, grape juice, wine, and other food sources. However, wine should not be used as a source of resveratrol during pregnancy and lactation.

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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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ACENOCOUMAROL (Sintrom) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, L-carnitine might increase the anticoagulant effects of acenocoumarol.  Details L-carnitine might enhance the anticoagulant effects of acenocoumarol, an oral anticoagulant similar to warfarin, but shorter-acting (9878,12165). There are at least two case reports of INR elevation with concomitant use. In one case, a 33-year-old male with a previously stable INR had an elevated INR of 4.65 after L-carnitine was started and continued for 10 weeks. INR normalized after discontinuation of the L-carnitine-containing product (12165).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, L-carnitine might decrease the effectiveness of thyroid hormone replacement.  Details L-carnitine appears to act as a peripheral thyroid hormone antagonist by inhibiting entry of thyroid hormone into the nucleus of cells (12761). Taking L-carnitine also seems to diminish some of the symptoms of hyperthyroidism (8047).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, L-carnitine might increase the anticoagulant effects of warfarin.  Details L-carnitine might increase the anticoagulant effects of acenocoumarol, a shorter-acting oral anticoagulant similar to warfarin (9878,12165). There is not enough information to know whether this interaction occurs with L-carnitine and warfarin.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Resveratrol may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Resveratrol seems to have antiplatelet effects (2949,2950,2951,2952,2961,70813,70828,70831,70892,70968,71106).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A1.  Details In vitro research shows that resveratrol can inhibit CYP1A1 enzymes (70811,70862). However, this interaction has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that resveratrol can inhibit CYP1A2 enzymes (21733). However, this interaction has not been reported in humans.

CYTOCHROME P450 1B1 (CYP1B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1B1.  Details In vitro research shows that resveratrol can inhibit CYP1B1 enzymes (70834). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP2C19.  Details In vitro research shows that resveratrol can inhibit CYP2C19 enzymes (70896). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Resveratrol might increase levels of drugs metabolized by CYP2E1.  Details In vitro research suggests that resveratrol inhibits CYP2E1 isoenzyme (7864,70896). Also, a pharmacokinetic study shows that taking resveratrol 500 mg daily for 10 days prior to taking a single dose of chlorzoxazone 250 mg increases the maximum concentration of chlorzoxazone by about 54%, the area under the curve of chlorzoxazone by about 72%, and the half-life of chlorzoxazone by about 35% (95824). Chlorzoxazone is used as a probe drug for CYP2E1.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that resveratrol can inhibit the CYP3A4 enzyme (7864,70896). However, clinical research shows that taking resveratrol 3000 mg daily for 8 weeks does not necessitate dose adjustments to medications metabolized by CYP3A4 (91327).

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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 and intravenously, L-carnitine is generally well tolerated.
Most Common Adverse Effects:
All routes of administration: Abdominal cramps, abdominal pain, diarrhea, gastritis, heartburn, nausea, reduced appetite, and vomiting. A fish-like body odor has also been reported.
Serious Adverse Effects (Rare):
All routes of administration: Seizures.

Cardiovascular ...According to population research, plasma L-carnitine levels are associated with increased risk of cardiovascular disease and major cardiac events (90635). However, oral supplementation with L-carnitine does not appear to be associated with an increased risk of cardiovascular disease. In fact, a meta-analysis of clinical research shows that L-carnitine supplementation is associated with a reduction in all-cause mortality, as well as ventricular arrhythmias and the development of angina and does not increase the development of heart failure or myocardial reinfarction (59037). Also, another meta-analysis suggests that L-carnitine does not affect mortality or cardiovascular outcomes in patients with a previous myocardial infarction (90630).

Dermatologic ...Orally, L-carnitine has been reported to cause skin rash in a small number of cases (16105,91724). Two patients in a hair growth study using topical carnitine reported mild itching and increased dandruff, while a third reported strong itching with reddish bumps and a burning sensation (58390). When a specific formulation containing L-carnitine, licochalcone, and 1,2-decanediol was applied to the face, mild skin dryness and tightness was reported by 12% of volunteers, compared with 4% to 8% of those in the vehicle-only control group (26493).

Gastrointestinal ...Orally and intravenously, L-carnitine has been associated with nausea, epigastric discomfort, vomiting, abdominal cramps, heartburn, gastritis, anorexia, and diarrhea (3616,3624,59030,95069,95070,101562,107410,111870,111887,111891). Orally, diarrhea or colitis symptoms (1433,3630,16105,16107,16111,23437,58523,58554,59020,90623), nausea and abdominal pain (16105,16106,26499,58169,58392,58554,90623,90634), indigestion (26703), and constipation (58523) have been reported in various clinical trials.

Hematologic ...In one case report, L-carnitine 990 mg twice daily was started in a female presenting to hospital with valproic acid toxicity. Blood phosphorous levels subsequently fell from 2.3 mg/dL to 1.3 mg/dL over 4 days. After discontinuation of L-carnitine, blood phosphorus levels increased to 1.8 mg/dL. The authors suggested that the role of L-carnitine in improved protein metabolism may play a role in the declining levels of phosphorous in the blood and increased risk of hypophosphatemia (90628).

Neurologic/CNS ...Orally or intravenously, L-carnitine has been associated with seizures (3616). Orally, use of L-carnitine in clinical trials has resulted in headache, although this event is rare (58554,95070,111891). L-carnitine may also cause agitation (95070).

Other ...Orally or intravenously, L-carnitine has been associated with a fish-like body odor (1433,3616,58166,59854,90623). One of its metabolites, trimethylamine N-oxide, can cause the urine, breath, and sweat to have a fishy odor (12756,58664).

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General ...In foods, resveratrol is well tolerated. When used orally in higher doses, as well as topically or intranasally, resveratrol seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, and loose stools.

Dermatologic ...Orally, there is one case of a pruritic skin rash that occurred in a clinical trial. The rash resolved two weeks after stopping resveratrol (109163).
Topically, a case of allergic contact dermatitis has been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing aqueous resveratrol 1% in combination with Baikal skullcap root extract 0.5%. Patch testing identified a positive reaction to both ingredients (110024).

Gastrointestinal ...Orally, mild gastrointestinal discomfort with increased diarrhea or loose stools has been reported, especially when resveratrol is taken in doses of 2. 5-5 grams daily (71042,71052,91327,95830,109163,109164,109167).

Hematologic ...In one clinical study, a patient developed severe febrile leukopenia and thrombocytopenia after taking oral resveratrol 500 mg three times daily for 10 days. Upon re-exposure to resveratrol, febrile leukopenia recurred (109163).

Musculoskeletal ...Orally, resveratrol has been associated with muscle cramps in patients on peritoneal dialysis. The causality of this adverse effect has not been established (95830).

Neurologic/CNS ...Orally, resveratrol has been associated with headache, fatigue, and memory loss in patients on peritoneal dialysis. The causality of these adverse effects has not been established (95830).

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