CellGen by Amkey

POSSIBLY EFFECTIVE

• Age-related cognitive decline. Oral acetyl-L-carnitine may improve age-related cognitive decline. Details: Clinical research shows that taking acetyl-L-carnitine 1500-2000 mg daily for 3 months seems to improve some measures of cognitive function and memory in elderly people with age-related cognitive decline (42,3600,3601).
• Age-related fatigue. Oral acetyl-L-carnitine may improve age-related physical and mental fatigue. Details: One clinical trial shows that taking acetyl-L-carnitine 2 grams twice daily for 180 days reduces physical fatigue by 52% and mental fatigue by 43%, compared with only 4% and 8%, respectively, for elderly patients taking placebo. Fatigue after exercise is also reduced by 51% in those taking acetyl-L-carnitine, compared with only 4% in those taking placebo (58375).
• Alcohol use disorder. Intravenous acetyl-L-carnitine may reduce cravings and other symptoms of withdrawal during alcohol detoxification. It is unclear if oral acetyl-L-carnitine is beneficial for managing withdrawal or complications of alcohol use disorder. Details: Clinical research in adults with alcohol use disorder who are in withdrawal shows that acetyl-L-carnitine 1-3 grams daily, administered as a slow intravenous infusion over 3-4 hours for 10 days, followed by 3 grams daily orally for an additional 80 days, improves cravings, the inability to feel pleasure (anhedonia), and melancholic symptoms and increases the time to the first drink when compared with placebo. However, most symptom improvement appears to occur during the first week, so it is unclear if taking acetyl-L-carnitine 3 grams daily orally for an additional 80 days is beneficial (90766,90767). One small clinical trial in adults with chronic alcohol use disorder and cognitive impairment shows that taking acetyl-L-carnitine 2 grams daily for 90 days seems to improve memory and visuospatial capacity when compared with placebo (1589).
• Alzheimer disease. Oral acetyl-L-carnitine may slow the progression of Alzheimer disease and improve some measures of cognitive function. Details: Clinical research shows that taking acetyl-L-carnitine 1.5-3 grams daily for 3-12 months might slow the rate of Alzheimer disease progression and improve memory, some measures of cognitive function, and behavioral performance. It is more likely to show some effect in those with early-onset Alzheimer disease who are less than 66 years of age and have a faster rate of disease progression and mental decline (1594,1595,1596,1597,1598,1599,9105,10391). It is unclear how acetyl-L-carnitine compares with prescription medications.
• Depression. Oral acetyl-L-carnitine may reduce symptoms of depression, with comparable effects to conventional antidepressants, in patients with dysthymia and depression. It may be most effective in elderly patients and at higher doses. Details: Several clinical trials addressing the use of acetyl-L-carnitine in elderly patients with dysthymia and depression have been conducted (3602,3603,3604). A meta-analysis of these and other studies, all conducted in Europe, shows that taking acetyl-L-carnitine 1-4 grams daily for 3-24 weeks moderately reduces depressive symptoms when compared with placebo, and appears to have similar effects as conventional antidepressants. Acetyl-L-carnitine seems to be most effective when used at higher dosages. Duration of follow-up and baseline symptoms do not appear to influence results (95065).
• Diabetic neuropathy. Oral acetyl-L-carnitine may reduce pain in patients with diabetic neuropathy when taken at doses of at least 2-3 grams daily. It is unclear if oral acetyl-L-carnitine can improve nerve conduction velocity in these patients. Details: Although most clinical research evaluating acetyl-L-carnitine for use in diabetic neuropathy has shown benefit, this evidence is of overall low quality. A meta-analysis shows that taking acetyl-L-carnitine 2-3 grams daily for up to 12 months modestly reduces pain scores by about 15 points on a 100-point visual analog scale, while lower doses of 1.5 grams daily improve pain scores to a similar extent as placebo. Some research included in this analysis shows that acetyl-L-carnitine seems to increase nerve fibers, regenerate nerve fiber clusters, and improve vibratory sensations. In two studies, vibration sensation improved after 12 months when compared with placebo, but numerical data are lacking (102126). Other clinical research shows that taking acetyl-L-carnitine 1000 mg 2-3 times daily decreases pain within 6 months. Acetyl-L-carnitine seems to be most effective for reducing pain in patients with a shorter duration of diabetes and in patients with poorly controlled type 2 diabetes. Some research shows that taking acetyl-L-carnitine 500 mg (Liaoning Haisike Pharmaceutical Co. Ltd.) three times daily for 24 weeks is as effective as methylcobalamin 0.5 mg three times daily for improving electrophysiological parameters and symptoms as measured by the Neuropathy Disability Score (95067,102126). However, research on the use of acetyl-L-carnitine to improve nerve conduction velocity in patients with diabetic neuropathy is conflicting (1593,12743,12753,13007,95067).
• Male infertility. Oral acetyl-L-carnitine, taken in combination with L-carnitine, may increase sperm motility in males with infertility. It is unclear if oral acetyl-L-carnitine alone can improve sperm function or pregnancy outcomes. Details: Although some research disagrees (111861), taking acetyl-L-carnitine in combination with L-carnitine, usually in doses of 1 gram and 2 grams, respectively, daily for 3-6 months seems to increase sperm motility in males with infertility of various etiologies. The evidence related to the effect of this combination on sperm count and morphology is mixed (12352,58182,58194,58469,101560,107394,111459,111890). However, it is unclear if taking L-carnitine increases the odds of pregnancy. One meta-analysis of randomized controlled trials shows that taking these carnitines 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). Taking acetyl-L-carnitine 500 mg and L-carnitine 1 gram twice daily after taking nonsteroidal anti-inflammatory drugs for 2 months seems to increase sperm count and motility in those with abacterial prostatovesiculoepididymitis, an inflammation of the prostate gland, seminal vesicles, and epididymis (9791). Acetyl-L-carnitine has also been evaluated in combination with other ingredients. One study shows that taking acetyl-L-carnitine 50 mg in combination with L-carnitine 150 mg, L-arginine 1660 mg, and Panax ginseng 200 mg daily for 3 months increases sperm motility and sexual satisfaction in those with asthenospermia 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 treatment with prulifloxacin alone in patients with chronic prostatitis due to Chlamydia trachomatis infection (59006). Other small and preliminary Iclinical studies have investigated the effects of a specific combination product providing acetyl-L-carnitine 500 mg twice daily for 6 months, along with 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.

POSSIBLY INEFFECTIVE

• Chemotherapy-induced peripheral neuropathy. The evidence related to the effect of oral acetyl-L-carnitine on symptoms of chemotherapy-induced peripheral neuropathy is mixed. Some research shows that it may actually worsen symptoms. Details: High quality clinical research in females treated with taxane-based therapy for early-stage breast cancer shows that taking acetyl-L-carnitine 1000 mg three times daily for 24 weeks does not improve symptoms of neuropathy when compared with placebo. In fact, acetyl-L-carnitine treatment may actually make symptoms worse in some patients, with worsened symptoms persisting for up to at least 2 years (90758,96938,111882). Also, a small clinical trial in patients with multiple myeloma receiving bortezomib, doxorubicin, and dexamethasone shows that taking acetyl-L-carnitine 1.5 grams daily does not reduce symptoms of peripheral neuropathy when compared with not taking acetyl-L-carnitine (90756). A small clinical trial in patients with ovarian cancer or castration-resistant prostate cancer receiving sagopilone shows that taking acetyl-L-carnitine 1000 mg every three days appears to reduce the more severe symptoms of peripheral neuropathy; however, the overall incidence or duration of peripheral neuropathy is not reduced when compared with placebo (90757). Some research disagrees. One clinical trial in patients with taxoid-related neuropathy shows that taking acetyl-L-carnitine3 grams daily for 8 weeks modestly improves the severity of neuropathy by at last one grade in 51% of patients compared with 24% of those taking placebo. Functional improvement was also modestly improved (111862). Based on the available research, the American Society of Clinical Oncology strongly discourages the use of acetyl-L-carnitine for the prevention of chemotherapy-induced peripheral neuropathy, noting that the harms outweigh the potential benefits (104168).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. Oral acetyl-L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in older males shows that taking acetyl-L-carnitine 2 grams, in combination with propionyl-L-carnitine 2 grams, daily for 6 months seems to attenuate symptoms of androgen decline. The combination appears to be similar to testosterone for improving sexual dysfunction, depression, and fatigue (12353). It is unclear if these findings are due to acetyl-L-carnitine, propionyl-L-carnitine, or the combination.
• Aging skin. Although there has been interest in using oral acetyl-L-carnitine for aging skin, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Amenorrhea. Although there has been interest in using oral acetyl-L-carnitine for amenorrhea, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral acetyl-L-carnitine is beneficial in patients with ALS. Details: One small clinical trial in patients with ALS shows that taking acetyl-L-carnitine 1000 mg three times daily for 48 weeks, along with riluzole 50 mg twice daily, reduces the number of patients who lose self-sufficiency by about 17%, increases patient survival by a median of 23 months, and improves some measures of physical function when compared with riluzole alone (90755).
• Antiretroviral toxic neuropathy. Small clinical studies suggest that oral acetyl-L-carnitine may modestly improve symptoms in patients with antiretroviral toxic neuropathy. It is unclear if intramuscular or intravenous acetyl-L-carnitine is beneficial in patients with this condition. Details: Small clinical trials show that taking acetyl-L-carnitine 1000-1500 mg twice daily for up to 33 months might relieve symptoms of distal symmetrical polyneuropathy caused by antiretroviral treatment in HIV-positive patients (12745,58342). Also, a small, uncontrolled clinical study shows that intramuscular or intravenous administration of acetyl-L-carnitine 500-1000 mg daily for 3 weeks reduces pain intensity when compared to baseline in some HIV-positive patients receiving antiretroviral therapy (12747). However, another clinical study shows that intramuscular acetyl-L-carnitine 500 mg twice daily for 14 days does not reduce pain when compared with placebo (58342).
• Athletic performance. Although there has been interest in using oral acetyl-L-carnitine for athletic performance, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Small clinical trials suggest that oral acetyl-L-carnitine is not beneficial in children with ADHD. Details: One small clinical trial in children and adolescents with ADHD shows that taking acetyl-L-carnitine 1-3 grams daily, based on body weight, in two divided doses along with methylphenidate 20-30 mg daily for 3 weeks does not reduce symptoms of ADHD when compared with methylphenidate alone (90754). Based on this and another small trial, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that acetyl-L-carnitine in doses of 1-3 grams daily is not recommended for adjunctive or monotherapy use for ADHD in children (110318).
• Bell palsy. Although there has been interest in using oral acetyl-L-carnitine for Bell palsy, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Bipolar disorder. Oral acetyl-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 type I or type II bipolar disorder 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 (90441).
• Cancer-related fatigue. Although there has been interest in using oral acetyl-L-carnitine for cancer-related fatigue, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Carpal tunnel syndrome. It is unclear if oral acetyl-L-carnitine is beneficial in patients undergoing surgery for carpal tunnel syndrome. Details: A small clinical study in adults undergoing carpal tunnel release surgery shows that taking acetyl-L-carnitine 3000 mg daily for 2 months postoperatively does not improve nerve regeneration or functional recovery when compared with placebo (100349). However, this study may have been inadequately powered to detect a difference between groups. Acetyl-L-carnitine has also been investigated in combination with other ingredients. In patients with mild to moderate symptoms awaiting carpal tunnel release, preliminary clinical research shows that taking acetyl-L-carnitine as part of a multi-ingredient formulation for 60 days reduces pain by 31%, but does not improve function, when compared with no treatment. The formulation provided a total of 600 mg twice daily of acetyl-L-carnitine with alpha-lipoic acid, phosphatidylserine, curcumin, thiamine, riboflavin, and vitamins C, E, B6, and B12 (111702).
• Cataracts. Although there has been interest in using oral acetyl-L-carnitine for cataracts, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Chronic fatigue syndrome (CFS). It is unclear if oral acetyl-L-carnitine is beneficial in patients with CFS. Details: Preliminary clinical research in patients with CFS shows that taking acetyl-L-carnitine 2 grams daily for 6 months improves general fatigue in up to 59% of patients when compared with baseline. The combination of acetyl-L-carnitine and propionyl-L-carnitine appears to be less effective than either supplement alone, with only 37% of patients taking this combination achieving improvement when compared with baseline (11788).
• Diabetes. It is unclear if oral acetyl-L-carnitine improves glycemic control in people with type 2 diabetes. Details: Clinical research in patients with type 2 diabetes, hypertension, and dyslipidemia shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve blood glucose levels, glycated hemoglobin, fasting insulin levels, insulin resistance, or glucose disposal rate when compared with placebo. Most patients were already taking one or more antidiabetes drug, as well as medication for hypertension and dyslipidemia (96937). It is unclear if acetyl-L-carnitine improves glycemic profile in patients with uncontrolled diabetes.
• Down syndrome. Although there has been interest in using oral acetyl-L-carnitine for Down syndrome, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Dyslipidemia. It is unclear if oral acetyl-L-carnitine reduces lipid levels in adults with dyslipidemia. Details: Clinical research in patients with dyslipidemia, type 2 diabetes, and hypertension shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve cholesterol, triglycerides, or lipoprotein(a) levels when compared with placebo. All patients were taking statins prior to treatment with acetyl-L-carnitine, and most were receiving medication for hypertension and diabetes (96937). It is unclear if acetyl-L-carnitine is beneficial in patients not taking statins.
• Fibromyalgia. It is unclear if oral and/or intramuscular acetyl-L-carnitine can improve symptoms of fibromyalgia. Details: One clinical study in patients with fibromyalgia shows that taking acetyl-L-carnitine 1000 mg daily orally plus acetyl-L-carnitine 500 mg daily intramuscularly for 2 weeks, followed by acetyl-L-carnitine 1500 mg daily orally for 8 weeks, reduces muscle pain and improves mood, general health, and quality of life when compared with placebo (90768). A smaller clinical study in patients with fibromyalgia shows that taking acetyl-L-carnitine 500 mg three times daily for 12 weeks improves quality of life (physical) scores and symptoms of depression, but not pain, anxiety, or quality of life (mental) scores when compared with baseline (90761). The validity of these findings is limited by the lack of a comparator group. Acetyl-L-carnitine has also been investigated in combination with other ingredients. Clinical research shows that taking acetyl-L-carnitine 500 mg and palmitoylethanolamide (PEA) 600 mg twice daily for 12 weeks increases the proportion of patients with at least a 30% reduction in pain by 86% when compared with not taking this combination. There was also a modest improvement in the overall assessment of status. All patients were on stable treatment with duloxetine and pregabalin for 3 months prior to the initiation of acetyl-L-carnitine and PEA, and this treatment continued throughout the study (111901).
• Fragile X syndrome. Small clinical studies suggest that oral acetyl-L-carnitine is not beneficial in children with fragile X syndrome. Details: Two small clinical studies in children with fragile X syndrome shows that acetyl-L-carnitine 20-50 mg/kg daily for one year does not improve intellectual function when compared with placebo. Also, while it may reduce hyperactive behavior in these patients based on parent assessment, it does not appear to reduce hyperactive behavior based on teacher assessment (9956,93063).
• Frailty. It is unclear if oral acetyl-L-carnitine prevents frailty. Details: Clinical research in pre-frail older adults shows that taking acetyl-L-carnitine 1.5 grams twice daily for 3 months modestly improves cognition and the distance walked in 6 minutes when compared with taking placebo (111889). It is unclear whether taking acetyl-L-carnitine is beneficial for frailty treatment or prevention.
• Hepatic encephalopathy. Small clinical studies suggest that oral acetyl-L-carnitine may not improve quality of life or fatigue in patients with hepatic encephalopathy due to cirrhosis. Details: The benefits of acetyl-L-carnitine in the management of hepatic encephalopathy due to cirrhosis are unclear (58922,58949,59002,90759). A meta-analysis of the available clinical research shows that taking acetyl-L-carnitine 2 grams twice daily for 90 days does not improve quality of life or fatigue in this population when compared with placebo. However, major clinical outcomes, such as all-cause mortality, days of hospitalization, and serious adverse events, have not been evaluated. Additionally, the validity of these findings is limited by the small size, high risk for bias, and heterogeneity of the included studies (100350).
• Hypertension. It is unclear if oral acetyl-L-carnitine lowers blood pressure in adults with hypertension. Details: Clinical research in patients with hypertension, type 2 diabetes, and dyslipidemia shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve systolic or diastolic blood pressure when compared with placebo. Most patients were already being treated with antihypertensive drugs prior to treatment with acetyl-L-carnitine, in addition to medications for dyslipidemia and diabetes (96937). It is unclear if acetyl-L-carnitine reduces blood pressure in patients with uncontrolled hypertension.
• Infertility. Although there has been interest in using oral acetyl-L-carnitine for infertility in females, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Lyme disease. Although there has been interest in using oral acetyl-L-carnitine for Lyme disease, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Multiple sclerosis-related fatigue. It is unclear if oral acetyl-L-carnitine is beneficial in patients with multiple sclerosis-related fatigue. Details: One small clinical study in patients with multiple sclerosis shows that taking acetyl-L-carnitine 1 gram twice daily for one month reduces fatigue by approximately 25% when compared with placebo (90760).
• Obesity. Although there has been interest in using oral acetyl-L-carnitine for obesity, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Peripheral neuropathy. Although there has been interest in using oral acetyl-L-carnitine for peripheral neuropathy, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Peyronie disease. A small clinical study suggests that oral acetyl-L-carnitine may modestly improve symptoms of Peyronie disease. Details: One small clinical trial in patients with acute and early chronic Peyronie disease shows that taking acetyl-L-carnitine 1 gram twice daily for 3 months reduces pain and slows disease progression when compared with tamoxifen 20 mg twice daily (10076).
• Polycystic ovary syndrome (PCOS). It is unclear if acetyl-L-carnitine is beneficial in patients with PCOS. Details: A clinical study in patients with PCOS shows that taking acetyl-L-carnitine 1.5 grams, in combination with metformin and pioglitazone, twice daily for 12 weeks improves menstrual irregularity and insulin resistance when compared with baseline. The lack of statistical comparison to placebo, as well as the combined use with metformin and pioglitazone, limits the validity of these findings (107396).
• Schizophrenia. It is unclear if oral acetyl-L-carnitine is beneficial in patients with schizophrenia. Details: A very small, open-label clinical study in patients with schizophrenia who partially responded to clozapine therapy shows that taking acetyl-L-carnitine 1 gram daily, in combination with clozapine 300-600 mg daily, for 12 weeks reduces positive symptoms of schizophrenia, but not cognitive function or other clinical symptoms, when compared with baseline (95063). The validity of these findings is limited by the lack of a comparator group.
• Sciatica. It is unclear if oral acetyl-L-carnitine is beneficial in patients with sciatica. Details: One small clinical trial in patients with sciatica secondary to a herniated disc shows that taking acetyl-L-carnitine (Nicetile, SigmaTau Ind. Farm. Riunite SpA,) 1180 mg daily for 60 days decreases the use of analgesics when compared with baseline. However, acetyl-L-carnitine appears to be less effective than alpha-lipoic acid (Byodiniral 300 QR, MDM SpA,) 600 mg daily for reducing lower limb pain and the use of analgesics (21671).
• Stroke. It is unclear if oral acetyl-L-carnitine is beneficial following a stroke. Details: Clinical research in patients with an acute ischemic stroke given routine care shows that oral or nasogastric acetyl-L-carnitine 1 gram three times daily for 3 days modestly improves stroke impairment and overall function 3 months after the stroke when compared with taking placebo. The proportion of patients taking acetyl-L-carnitine with no symptoms or obvious disability at 3 months was 53%, compared with 29% of patients taking placebo. The patients in this study were not candidates of reperfusion therapy and initiated acetyl-L-carnitine within 24 hours of the stroke (111894).
• Toxin-induced liver damage. Oral acetyl-L-carnitine 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 acetyl-L-carnitine 250 mg, along with coenzyme Q10 and alpha-lipoic acid, 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 acetyl-L-carnitine, other ingredients, or the combination. More evidence is needed to rate acetyl-L-carnitine for these uses.

(Read more about ACETYL-L-CARNITINE)

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)

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CHOLINE)

POSSIBLY EFFECTIVE

• Athletic performance. Oral creatine monohydrate seems to modestly improve rowing, jumping, and soccer performance. It is unclear if it is beneficial for sprinting, cycling, swimming, or tennis performance. Details: In competitive rowers, most clinical research shows that taking creatine 20 grams or 240-250 mg/kg daily for 5 days significantly improves aerobic and anaerobic performance (4605,4607,46569,46605,46833). Specifically, creatine decreases 1000-meter rowing time by 2.4 seconds and 2500-meter rowing time by 6.5 seconds and increases time to fatigue by 9.7 seconds when compared with placebo (4607,46605,46833). To improve rowing performance, creatine 20 grams (or 240-250 mg/kg) daily for 5 days has been used (4605,4607,46605,46833). Additionally, most clinical research shows that taking creatine 20-30 grams daily for 5-7 days improves jumping height by up to 6 cm when compared with placebo in active males (11331,13661,46626,46704), although some conflicting results exist (6924,46601). When compared with placebo, creatine also appears to improve spike jumping and block jumping in male volleyball players (46762), as well as peak and mean power of stationary roundhouse kicks in male trained taekwondo athletes (108333). In young male soccer players, preliminary clinical research shows that taking creatine 10 grams three times daily for 7 days can increase performance on a specific dribbling speed test by up to 2.8 seconds when compared with placebo (46626). In young female soccer players, preliminary clinical research shows that taking creatine 5 grams four times daily for 7 days followed by 5 grams daily for 5 weeks in conjunction with plyometric training modestly increases body mass index, jump and power performance, and repeated sprinting performance when compared with either plyometric training with placebo or standard soccer drills (95961). Research evaluating creatine supplementation for sprinting, cycling, high-intensity-interval training (HIIT), and swimming has been inconsistent. The reason for these mixed findings is unclear. A meta-analysis of small clinical trials shows that taking creatine decreases the peak oxygen uptake (VO2 max) during running and cycling, suggesting a worsening of aerobic fitness (108330). However, another meta-analysis of randomized controlled trials shows that taking creatine up to 20 grams orally daily for 3-7 days modestly improves mean power, but not peak power or fatigue, during repeated running or cycling sprint intervals when compared with placebo (112206). In addition, a meta-analysis of randomized clinical trials in trained athletes shows that taking creatine up to 20 grams orally daily for 5-42 days does not improve endurance running or cycling performance when compared with control (112214). A potential explanation for these conflicting results is that the studies failing to show an improvement are likely underpowered, with sample sizes of only 6-32 subjects (4582,4601). For instance, some small clinical trials show that taking creatine 20-30 grams daily for 5-7 days can improve sprint times by up to 3% and decrease time to exhaustion by up to 13% when compared with placebo in trained athletes (6924,11331,46558,46567,46626,46819); however, others show that taking creatine 20-25 grams daily for 3-7 days does not improve sprint velocity, 60-meter or 150-meter sprint times, or fatigue in these individuals (46603,46656,46797,46806,112216). In trained athletes, untrained yet healthy adults, and sedentary adults, some clinical research shows that taking creatine 10-35 grams daily for 4-7 days significantly improves power output, peak power, and fatigue indices while cycling (4591,4592,4593,4594,4602,4604,6926,10064,46522,46528) (46547,46568,46601,46614,46820); however, significant improvements in cycling performance with creatine are lacking in other studies (4582,4595,4596,4597,4598,4599,4600,4606,46520,46538) (46646). Similarly, in trained swimmers, some clinical research shows that creatine improves swimming performance (4601,4603,46600,46655,46725,46805), with a few studies reporting improvements of 1.3-2 seconds in 100-meter swim times when compared with placebo (46600,46725,46805). However, creatine does not improve 25-, 50-, or 100-meter swim performance in other trials (2106,4601,46798). To improve swimming performance, creatine 9-25 grams daily for 4-9 days has been used (4601,4603,46600,46655,46725,46805), with lower maintenance doses of 2.25-10 grams daily for 8-9 days used in some cases (4601,46600). Preliminary clinical research in trained tennis players shows that taking creatine 5 grams four times daily for 5 days or 0.3 grams/kg daily for 6 days followed by 0.03 grams/kg daily for 4 weeks does not appear to improve stroke power, stroke precision, serving speed, sprinting, or shuttle run time when compared with placebo (46536,46673). Taking creatine (Creapure, AlzChem AG) 0.3 grams/kg daily for 5 days, followed by 0.1 grams/kg daily for 23 days, while undergoing HITT 3 days each week does not improve physical performance outcomes when compared with placebo in healthy young females (95965). A preliminary clinical trial in elite female handball players shows that the beneficial effects of creatine monohydrate 0.3 grams/kg for 5 days followed by 0.03 grams/kg are not dependent on the time of day of supplementation (108332). Although this suggests that the circadian rhythm does not influence the ergogenic effect of creatine, this study was small and may have been underpowered to detect any differences. One clinical study compared the efficacy of creatine monohydrate with that of creatine nitrate. At equivalent doses of 12 grams daily for 7 days, followed by 3 grams daily for 21 days, creatine nitrate and creatine monohydrate produce similar increases in fat-free mass, lean mass, and intramuscular creatine concentrations, and similar improvements in bench press lifting volume and average power output. The lower dose of creatine nitrate 6 grams daily for 7 days followed by 1.5 grams daily for 21 days does not demonstrate performance improvement benefits or result in increased intramuscular creatine (95959). In 2018, the International Society of Sports Nutrition (ISSN) recommended creatine monohydrate, but not creatine nitrate, as an ergogenic nutritional supplement for increasing athletic capacity and lean body mass (101009). Creatine has also been evaluated in combination with a variety of other ergogenic supplement ingredients. However, research is conflicting and variable and any benefits may be dose- and/or population-dependent.
• Cerebral creatine deficiency syndromes. Oral creatine seems to improve some symptoms of the cerebral creatine deficiency syndromes guanidinoacetate methyltransferase (GAMT) deficiency and arginine-glycine amidinotransferase (AGAT) deficiency. It is unclear if oral creatine is beneficial for creatine transporter defect. Details: Three inborn errors of metabolism, GAMT deficiency, AGAT deficiency, and creatine transporter defect, cause low cerebral creatine levels, resulting in mental retardation, seizures, autism, and movement disorders. In children with GAMT deficiency, taking creatine orally, 400-500 mg/kg daily for up to 8 years or 4-8 grams daily for up to 25 months, increases brain creatine levels and improves movement disorders and seizure frequency, but has little effect on intellectual ability (46722,46796,46804). Children with AGAT deficiency who take creatine 400-800 mg/kg daily for up to 8 years seem to have improved attention, language development, and academic performance (46584,46769). However, research in children up to 10 years of age with creatine transporter defect shows that taking a mixture of creatine, L-arginine, and glycine orally for 4-6 years does not increase brain creatine levels or improve motor or cognitive functioning (46757).
• Muscle strength. Oral creatine seems to modestly improve muscle strength. It is unclear if topical creatine is beneficial. Details: Pooled analyses of clinical trials assessing upper limb strength, lower limb strength, and body composition have evaluated creatine provided in typical loading doses of 20 grams daily or 0.3 grams/kg daily, although doses up to 26 grams daily have been used, in single or divided doses for 5-7 days (90323,90330,93626,93627,108316,108336,112213). Creatine maintenance doses ranged from 1.25-27 grams daily for up to 24 weeks (90323,90330,93626,93627,108316,108336). In some studies, creatine doses of usually 0.1 grams/kg have been taken daily for up to 12 months in the absence of a loading dose. In others, creatine was taken only on training days (108316). Meta-analyses of research in the general adult population show that taking creatine with or without resistance training seems to improve upper limb strength and lower limb strength, with a small-to-moderate overall effect (93626,93627). Benefits in combination with resistance training have also been shown on upper and/or lower limb strength in older adults, although benefits on both have not been demonstrated in all analyses (90323,90330,108316,108336). A meta-analysis limited to studies involving older females shows that while taking creatine with resistance training increases upper body strength when compared with placebo, improvements to lower body strength are limited to those studies providing supplementation for at least 24 weeks (108336). Meta-analyses of studies involving middle-aged and older adults show that creatine supplementation combined with resistance training appears to increase total body mass by 1 kg and lean body mass by 0.9-1.3 kg when compared with placebo (90323,90330,108316). However, a meta-analysis of studies limited to older females shows that there was no effect of creatine on muscle mass (108336). Also, significant decreases in fat mass are lacking and effects on body fat percentage are inconsistent (90323,108335). While the analyses above provide a good estimate of creatine's effect on muscle strength, it is important to note that a large number of clinical trials assessing strength in patients taking creatine have been published. These studies included varying methodologies, small sample sizes, and a wide range of creatine doses, dosing times, and study durations. These differences may explain why some studies have found a benefit with creatine supplementation (2100,2101,4580,6015,6924,6928,10062,13661,46507,46510)(46523,46528,46550,46551,46561,46562,46567,46570,46581,46589)(46601,46613,46615,46618,46626,46628,46667,46709,46720,46725)(46761,46762,46801,46815,90321,90327,95958,95960,102162,103279)(104668,104670,108329,112213), while others have not (4569,4570,4571,4572,4588,6183,46520,46539,46554,46569)(46579,46594,46656,46665,46673,95963,95967,95968,95969,102168,104669)(104671,108334). Topical creatine has also been evaluated. Applying 3.5 mL of a specific cream (Delivra, LivCorp Inc.) containing creatine 1% daily for 7 days moderately improves peak and average muscle power in males when compared with a placebo cream. However, some study participants were also taking oral creatine monohydrate 7 grams three times daily and others were taking an oral placebo. An acute application of the cream at doses of 3.5 mL or 7 mL 30 minutes before exercise does not seem to improve power (104669).
• Sarcopenia. When used for up to 12 weeks in combination with resistance training, oral creatine seems to modestly improve muscle strength in older adults. It is unclear if oral creatine is beneficial when used as a single dose or for more than 12 weeks. Details: Most research shows that taking creatine while taking part in a resistance training program can increase upper and/or lower body muscle strength in older adults (90323,90330,95958,102162,108316,108336). One meta-analysis of research in adults 50 years of age and older taking part in resistance training programs shows that creatine supplementation improves chest press strength with a moderate effect size, but does not improve leg press strength, when compared with placebo (90330). Also, another meta-analysis focusing on adults 45 years of age and older taking part in resistance training shows that creatine supplementation improves chest press strength by 1.74 kg and leg press strength by 3.25 kg when compared with placebo, with no effect on knee extension or biceps curl measurements (90323). A meta-analysis limited to studies involving older females shows that while taking creatine with resistance training increases upper body strength when compared with placebo, improvements to lower body strength are limited to those studies providing supplementation for at least 24 weeks (108336). However, some negative findings exist. Some clinical research in postmenopausal females with osteopenia shows that taking creatine monohydrate 1-3 grams (Creapure, AlzChem AG) daily for 1-2 years without participation in resistance training does not alter muscle function when compared with placebo (95969,102168). In addition, in healthy males aged 49-69 years, a small clinical trial shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily, while undergoing supervised resistance training three days each week for one year, does not alter muscle strength when compared with placebo (104671). One clinical study shows that a single loading dose of creatine monohydrate 20 grams (Creapure, AlzCHem AG) taken 3 hours prior to exercise does not improve leg press or chest press muscle endurance in aging males (95968). Also, lower doses of creatine added to whey protein supplementation do not seem to be beneficial. One small study in adults 65 years or older shows that adding creatine monohydrate 2.5 grams twice daily along with whey protein 10 grams twice daily and resistance training for 14 weeks does not improve muscle function when compared with whey protein and resistance training alone (95966). Most research also suggests that creatine improves total muscle mass in older adults, although conflicting research exists. Some studies show that taking creatine while taking part in a resistance training program seems to increase muscle mass in older adults (90323,90330,108316,108329). Meta-analyses of studies involving middle-aged and older adults show that creatine supplementation combined with resistance training appears to increase total body mass by 1 kg and lean body mass by 0.9-1.3 kg when compared with placebo (90323,90330,108316). However, a meta-analysis of studies limited to older females shows that there was no effect of creatine on muscle mass (108336). Also, in healthy males aged 49-69 years, a small clinical trial shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily, while undergoing supervised resistance training three days each week for one year, does not alter body composition when compared with placebo (104671). Despite these generally beneficial findings, significant decreases in fat mass following creatine supplementation in older adults are lacking, and effects on body fat percentage are inconsistent (90323,95958,108335).

POSSIBLY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Oral creatine does not seem to reduce ALS symptoms or increase survival. Details: Taking creatine orally, 5-10 grams daily for 9-16 months, or 20 grams daily for 5-7 days followed by 3-5 grams daily for 6 months, has no effect on disease progression, respiratory function decline, or survival in patients with ALS (11332,16389,46553,46574,46707). In one case series, some patients experienced temporary improvement in muscle strength while taking 20 grams daily during the first week, but this was not maintained (46553).
• Huntington disease. Oral creatine does not seem to reduce symptoms of this condition. Details: Taking creatine orally has no effect on motor function or symptom scores in people with Huntington disease (46598,46609,95957). Clinical research shows that taking creatine 5-40 grams daily (average dose of 31.6 grams) for 24 months does not improve total motor score or total functional capacity in patients with early manifest Huntington disease (95957).
• Osteopenia. Oral creatine does not seem to be beneficial for osteopenia. Details: In postmenopausal adults with osteopenia, taking creatine monohydrate (Creapure, AlzChem GmbH ) 1-3 grams daily for 1-2 years does not improve bone mineral density (BMD) when compared with placebo (95969,102168). Another clinical trial in postmenopausal adults with osteopenia or osteoporosis shows that taking creatine monohydrate (Probiotica) 20 grams daily for 5 days and then 5 grams daily for the next 23 weeks, with or without exercise training, does not improve bone mass when compared with placebo (90321). Also, a small clinical trial in older adults, most of which had osteopenia, shows that taking creatine monohydrate (Rivalus Inc.) 0.05 grams/kg twice daily in combination with resistance training for 12 months modestly improves some measures of bone area, but not BMD, when compared with placebo (108329). Other research has evaluated creatine in patients without a definite diagnosis of osteopenia. One study shows that taking creatine (Rivalus Inc.) 0.1 gram/kg daily for 12 months or creatine (Creapure AlzChem Trostberg GmbH) 0.1 grams/kg three times weekly does not affect BMD in adults age 50 and up taking part in resistance training (104671,104674). In contrast, a small clinical trial in postmenopausal patients shows that taking creatine monohydrate (Rivalus Inc.) 0.1 gram/kg daily for 12 months while undergoing a resistance training program has a small preventive effect on bone loss at the femoral neck, but not the hip or spine (104673). However, other preliminary clinical research in postmenopausal patients shows that taking creatine (Creapure, AlzChem AG) 0.14 grams/kg orally daily for 2 years does not improve BMD when compared with placebo (112219). Also, preliminary clinical research shows that taking creatine 0.3 grams/kg for 5 days and 0.07 grams/kg for the remainder of a 12-week resistance training session increases BMD in elderly males over 70 years (46664). More information is needed to determine if creatine is beneficial when used in combination with a resistance training program in older adults.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral creatine is beneficial for the treatment or prevention of age-related cognitive decline. Details: Population research in the US has found a positive association between dietary creatine intake and a specific measure of cognitive function, the WAIS III Digit Symbol Substitution Test (DSS). In addition, this measure of cognitive function was highest in individuals who consumed more than 0.95 grams daily (108331). However, clinical research is conflicting. A small clinical trial in older adults shows that taking creatine monohydrate (Creapure, Deguss AG) 5 grams four times daily for one week has modest beneficial effects on some measures of cognitive function, but not others, when compared with baseline or placebo (46686). Another small clinical trial shows that taking creatine monohydrate 5 grams four times daily for five days, and then 5 grams daily for a total of 4 weeks, does not improve cognitive function when compared with placebo (108339).
• Aging skin. Topical creatine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a cream containing creatine 0.2%, guarana 0.4%, and glycerol 8% to the face daily for 6 weeks reduces wrinkles and skin sagging when compared to baseline (46766). Other research shows that a specific cream containing creatine 0.2% and folic acid 0.03% (Nivea Visage DNAage, Beiersdorf AG) reduces wrinkles and roughness and improves firmness of photo-aged skin when compared to baseline (46696). The effect of topical creatine alone on aging skin is unclear. Also, the validity of these findings is limited by the lack of a comparator group.
• Arsenic poisoning. It is unclear if oral creatine is beneficial in patients with arsenic poisoning. Details: Preliminary clinical research in adults regularly consuming well water that contains arsenic shows that taking creatine 3 grams orally daily for 12 weeks lowers the concentration of certain serum arsenic metabolites when compared with control (112212). Creatine has not been studied for management of acute arsenic poisoning.
• Chronic kidney disease (CKD). It is unclear if oral creatine is beneficial in patients with CKD. Details: A small clinical study in CKD patients undergoing hemodialysis shows that taking creatine monohydrate 20 grams daily for a week alternating with taking 5 grams daily for a week, for a total of 4 weeks, attenuates loss of lean body mass and reduces the malnutrition-inflammation score when compared with taking a maltodextrin control (102166).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral creatine is beneficial in patients with COPD. Details: One clinical study shows that taking creatine 22 grams daily for 5 days, then 3.76 grams daily for 6 weeks, does not improve pulmonary function or walking distance when compared with placebo (46699). Another study shows taking creatine 5.7 grams three times daily for 2 weeks, then once daily thereafter, improves patient self-assessment of lung function, but not exercise capacity, when compared with placebo (46658). A third study shows taking creatine 0.3 grams/kg for 7 days, then 0.07 grams/kg for 7 weeks, improves walking time, but not measures of lung function, when compared with placebo (46691). A meta-analysis of the results from these and other clinical trials shows that creatine does not improve exercise capacity, muscle strength, or quality of life in COPD patients. However, the studies analyzed were of varying quality, which may limit the validity of these findings (46740).
• Cognitive function. It is unclear if oral creatine is beneficial for improving cognitive function. Details: Some preliminary clinical research in healthy adults shows that taking creatine possibly improves some measures of cognitive performance, specifically short-term memory and reasoning. However, findings related to most measures of cognitive function are inconsistent (108340). Other preliminary clinical research in healthy adults shows that taking a specific creatine (Creapure, AlzChem) 10-20 grams orally daily for 6 weeks does not improve cognitive function scores when compared with placebo (112215).
• Congestive heart failure (CHF). It is unclear if oral creatine is beneficial in patients with CHF. Details: Two very small clinical studies show that taking creatine orally 20 grams daily for 5-10 days improves skeletal muscle strength and endurance, but not ejection fraction or symptoms of CHF, when compared with placebo (4562,4563). Also a small clinical study in males with class II-IV heart failure shows that taking creatine 5 grams daily for 6 months does not improve exercise capacity or ejection fraction when compared with placebo (90328). However, it is possible that these small studies were inadequately powered to detect a difference in these clinical outcomes.
• Depression. It is unclear if oral creatine is beneficial for improving symptoms of depression. Details: Preliminary clinical research shows that taking creatine 5 grams daily for 8 weeks improves response to escitalopram in females with major depressive disorder. Hamilton Depression Rating Scale (HAM-D) scores decreased by 80% when compared to baseline in those receiving creatine plus escitalopram, compared to a decrease of only 63% in those taking placebo plus escitalopram (46777). However, the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce recommend against use of creatine for depression until more conclusive data are generated (110318).
• Diabetes. It is unclear if oral creatine is beneficial for glycemic control. Details: A meta-analysis of preliminary clinical research shows that taking creatine does not affect levels of fasting blood glucose or measures of insulin resistance when compared with placebo (108338). However, most of the studies included in this analysis were not conducted in individuals with diabetes. In people with newly-diagnosed type 2 diabetes, preliminary clinical studies show a reduction in postprandial glucose levels after taking creatine 3-6 grams orally daily for 5 days (46732,46760). The studies show that creatine 3 grams once daily has similar effects to glyburide 3.5 mg daily, and that creatine 3 grams twice daily is similar to metformin 500 mg twice daily. The effects of treatment for longer than 5 days in patients with diabetes are unknown. However, in sedentary males without diabetes, taking creatine 10 grams daily for 3 months seems to improve glucose tolerance (46682).
• Fatigue. It is unclear if oral creatine is beneficial for cognitive fatigue prevention. Details: A small clinical study in healthy young adults with mental fatigue shows that taking creatine monohydrate (Sportimaxx) 20 grams daily for 7 days improves accuracy on prolonged cognitive tasks, but not cognitive measures that require a quick response, when compared with placebo (102170).
• Fibromyalgia. It is unclear if oral creatine is beneficial for improving exercise performance in patients with fibromyalgia. Details: Preliminary clinical research shows that taking creatine 5 grams orally four times daily for 5 days, followed by 5 grams daily for a total of 16 weeks, improves leg press strength by 10% and chest press strength by 8% when compared with placebo in patients with fibromyalgia. However, creatine supplementation does not appear to improve aerobic capacity, pain, sleep, quality of life, or cognitive function (90331).
• Gyrate atrophy. Anecdotal reports suggest that oral creatine may be beneficial in some patients with gyrate atrophy. Details: Gyrate atrophy of the choroid and retina is associated with elevated plasma ornithine levels, which inhibit creatine synthesis and result in muscle fiber atrophy and eye fundus damage. Left untreated, patients with this condition progressively lose their vision (4577,4578). A small case series suggests that taking creatine 1.5 grams daily for one year might slow eye damage and visual deterioration in some patients with this condition when compared to baseline (4578). The validity of this finding is limited by the small sample size and lack of a comparator group.
• Hereditary motor and sensory neuropathy. It is unclear if oral creatine is beneficial in patients with hereditary motor sensory neuropathies. Details: Preliminary clinical studies in people with hereditary motor sensory neuropathies, such as Charcot-Marie-Tooth Disease, suggest that taking creatine orally 5 grams daily for 1-12 weeks has no effect on muscle strength, endurance, or functional capacity when compared with placebo (46548,46630,46675,46695).
• HIV/AIDS-related wasting. It is unclear if oral creatine is beneficial in patients with muscle wasting associated with HIV. Details: A small clinical study shows that taking creatine orally 20 grams daily for 5 days, then 4.8 grams daily for 14 weeks, does not increase muscle mass or strength in patients with HIV with muscle wasting when compared with placebo (46718).
• Hyperhomocysteinemia. It is unclear if oral creatine is beneficial in patients with hyperhomocysteinemia. Details: Preliminary clinical research in strict vegan adults with hyperhomocysteinemia shows that taking micronized creatine monohydrate (Bioderm) 5 grams daily for 3 weeks reduces blood levels of homocysteine by 39% when compared with baseline (102169). The validity of this finding is limited by the lack of a comparator group.
• Inflammatory myopathies. It is unclear if oral creatine is beneficial in patients with idiopathic inflammatory myopathies. Details: Preliminary clinical research in people with dermatomyositis or polymyositis shows that taking creatine orally 20 grams daily for 8 days, followed by 3 grams daily for a total of 6 months, in addition to an exercise program, decreases aggregate functional performance time by around 7% and increases shoulder abduction and hip flexion strength when compared with placebo. However, no improvements in functional index or strength as measured by elbow flexion, knee extension, or dorsi flexion are reported (15520). Taking creatine does not seem to improve muscle strength or disease activity in patients aged 7-18 years with juvenile dermatomyositis. Preliminary clinical research shows that taking creatine (AlzChem) for 4 weeks to 6 months does not improve muscle strength or disease activity when compared with placebo. The doses used in this study were 150 mg/kg daily for children weighing up to 40 kg or 4.69 grams/m2 for those weighing over 40 kg (104672).
• Juvenile idiopathic arthritis (JIA). Oral creatine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In children with JIA, taking a specific supplement (Kre-Celazine; All American Pharmaceutical) containing creatine and fatty acids 750 mg twice daily for 30 days may improve pain and inflammation when compared to baseline. Pain scores were reduced to 0 or 1 in 81% of these patients, and laboratory measures of inflammation were normalized in nearly every patient (90322). However, the effect of creatine alone in JIA patients is unclear. Also, the validity of this study is limited by a lack of control group.
• McArdle disease. It is unclear if oral creatine is beneficial for this condition. Details: There is some preliminary clinical evidence that taking creatine orally, 150 mg/kg daily for 5 days, followed by 60 mg/kg daily for 5 weeks, improves frequency and/or severity of muscle pain in some, but not all, patients with McArdle disease (70). However, continuing with the higher dose of 150 mg/kg daily throughout the 5-week period seems to INCREASE muscle pain and exercise intolerance (46564).
• Memory. It is unclear if oral creatine is beneficial for improving memory. Details: A meta-analysis of randomized controlled trials in healthy adults shows that taking creatine 2.2-20 grams orally for 5 days to 24 weeks improves performance on certain memory tests when compared with placebo (112202). However, the validity of this study is limited by high heterogeneity. In addition, the statistical methods utilized in this meta-analysis are likely to increase the risk of false positive results (112203) and re-analysis using other methods failed to reproduce the significant effects of creatine (112204).
• Mitochondrial myopathies. It is unclear if oral creatine is beneficial in patients with mitochondrial myopathies. Details: Preliminary studies using creatine orally for mitochondrial myopathies, such as chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome, show mixed results. Using 150 mg/kg daily for 6 weeks or 20 grams daily for 4 weeks does not improve muscle function, exercise performance, or ease of completing activities of daily living when compared with placebo (46529,46650,104675). However, one very small clinical study shows that taking creatine 5 grams twice daily for 14 days, then 2 grams twice daily for 7 days, improves some measures of strength during high-intensity anaerobic and aerobic exercise, but not low-intensity exercise, when compared with baseline (4565).
• Multiple sclerosis (MS). It is unclear if oral creatine is beneficial in patients with MS. Details: A very small clinical study shows that taking creatine 20 grams orally daily for 5 days does not improve exercise capacity in people with relapsing-remitting multiple sclerosis when compared with placebo (46599).
• Muscle breakdown. It is unclear if oral creatine is beneficial for muscle breakdown prevention. Details: Preliminary clinical research shows that taking creatine 5 grams four times daily for 7 days seems to help maintain muscle mass and reduce loss of muscle strength associated with immobilization by a cast in young males aged 18-25 years (46713).
• Muscle cramps. It is unclear if oral creatine is beneficial in patients with muscle cramps related to hemodialysis. Details: Preliminary clinical research shows that taking creatine 12 grams orally 5 minutes before hemodialysis sessions for 4 weeks reduces the frequency of muscle cramps by around 60%, from an average of 6.4 episodes to 2.6 episodes over the course of 4 weeks of dialysis. No reduction in muscle cramp frequency is reported with placebo in these patients (46582).
• Muscular dystrophy. The evidence for the use of oral creatine in patients with various forms of muscular dystrophy is conflicting. Details: Preliminary studies have assessed oral creatine in patients with muscular dystrophy, including Duchenne dystrophy, Becker dystrophy, facioscapulohumeral dystrophy, sarcoglycan-deficient limb girdle muscular dystrophy, and myotonic dystrophies. Although a meta-analysis of available research shows that there is a small benefit of creatine on muscle strength in patients with muscular dystrophies, results of individual clinical trials have been inconsistent (104675). Some preliminary clinical research shows that measures of muscle strength or fatigue are improved after 8-16 weeks of treatment with creatine 3-5 grams or 0.1 gram/kg daily (6182,46596,46629,46739). Also, subjective improvement in muscle strength occurs in some people taking creatine 20 grams daily for one week, followed by 5 grams daily for 8 weeks (46639). The ability to perform activities of daily living improves only modestly, if at all (6182,46629,46739). Despite these positive results, some conflicting results exist. Some studies show no improvement in muscle strength or functional capacity with doses of 5 grams daily for 17-26 weeks (46616,46657), or 10.6 grams daily for 10 days followed by 5.3 grams daily for a total of 8 weeks (46587). Also, a dose of 10 grams daily for 12 weeks does not appear to improve muscle strength, although it seems to improve myalgia in some patients (10654). The inconsistent results reported in patients with muscular dystrophy may be explained by the different types of muscular dystrophies, the varied methodologies, or the small number of patients assessed. Studies failing to show an improvement with creatine may be underpowered, with sample sizes of only 20-60 (10654,46657).
• Neonatal apnea. It is unclear if oral creatine is beneficial for neonatal apnea treatment. Details: A preliminary clinical study shows that giving creatine orally 200 mg/kg daily for 2 weeks to premature infants with a gestational age of less than 32 weeks does not improve signs or symptoms of apnea of prematurity when compared with placebo (46623).
• Osteoarthritis. It is unclear if oral creatine is beneficial in patients with osteoarthritis. Details: In patients with osteoarthritis of the knee, preliminary clinical research shows that taking creatine 20 grams orally daily for one week, followed by 5 grams daily for 11 weeks, in combination with strengthening exercises, modestly improves physical functioning as measured by the number of stand-ups performed from a standard-height chair in 30 seconds when compared with exercise alone. Stiffness, pain, and quality of life were also improved with creatine supplementation; however, it is unclear if these improvements were significant when compared with exercise alone (46753).
• Parkinson disease. It is unclear if oral creatine is beneficial in patients with this condition. Details: Preliminary clinical research shows that taking creatine 5 grams twice daily for 12-18 months decreases the rate of disease progression when compared with placebo in patients who have not started conventional medications for symptom control (15353,46703). However, preliminary clinical research in patients with more advanced disease who have already started conventional medications shows that taking creatine 20 grams daily for 6 days followed by 2 grams daily for 6 months, and then 4 grams daily for 18 months does not decrease overall progression of symptoms or the need to start symptomatic treatment. However, increases in dopamine agonist doses were 3-fold lower over the course of the study in patients receiving creatine when compared with placebo (15354).
• Peripheral arterial disease (PAD). It is unclear if oral creatine is beneficial in patients with PAD. Details: A small clinical trial in patients with PAD shows that taking creatine monohydrate (Creapure, AlzChem Trostberg GmbH) 5 grams four times daily for one week, followed by 5 grams daily for the next 7 weeks, does not improve functional capacity based on walking distance, upper body strength, or lower body strength, when compared with placebo (108337). This study may have been inadequately powered to detect differences between groups.
• Post-stroke fatigue. It is unclear if oral creatine is beneficial in patients with post-stroke fatigue. Details: Very preliminary clinical research in patients undergoing progressive resistance training after a stroke shows that taking a specific creatine supplement (Creapure, AlzChem Trostberg GmbH) 0.3 grams/kg orally daily for 7 days, followed by 0.1 grams/kg orally daily for a total of 10 weeks modestly improves 6-minute walk test distance when compared with placebo (112207).
• Postoperative recovery. Small clinical studies suggest that oral creatine may not improve recovery of muscle strength after knee surgery. Details: Preliminary clinical research shows that taking creatine 20 grams daily for 7 days, followed by 5 grams daily for 11 weeks, does not improve recovery of muscle strength after anterior cruciate ligament (ACL) reconstruction surgery in young adults when compared with placebo (46622). Other preliminary research shows that taking creatine 10 grams daily for 10 days before total knee arthroplasty, followed by 5 grams daily for 30 days after surgery, does not improve muscle strength or functional recovery when compared with placebo (46659). These studies are limited by small size and variability in patient population and supplementation regimen.
• Rett syndrome. It is unclear if oral creatine is beneficial in patients with this condition. Details: Preliminary clinical research shows that taking creatine 200 mg/kg daily for 6 months does not improve symptom scores when compared with placebo in patients aged 3-25 years with Rett syndrome (46759).
• Rheumatoid arthritis (RA). Oral creatine does not seem to improve disease activity in patients with RA, but it might improve muscle strength. Details: Clinical research in adults with RA shows that taking creatine increases lean muscle mass, total body mass, and muscle strength, but does not alter disease activity or improve strength or physical function, when compared with placebo or a control group (6929,95964). Creatine was taken as 5 grams four times daily for 5 days, followed by 3 grams daily for 12 weeks, in one study and 5 grams four times daily for 5 days, followed by 0.5 grams four times daily for 16 days, in the other study (6929).
• Schizophrenia. It is unclear if oral creatine is beneficial in patients with schizophrenia. Details: Preliminary clinical research shows that taking creatine orally, 3 grams daily for one month followed by 5 grams daily for 2 months, does not improve symptom control or cognitive function in patients with schizophrenia when compared with placebo (16390).
• Spinal cord injury. It is unclear if oral creatine is beneficial in patients with spinal cord injury. Details: Preliminary clinical research shows that taking creatine orally, 20 grams daily for 7 days, increases exercise capacity by improving respiratory function in patients with spinal cord injury (cervical level C5-7) when compared with placebo (46563). However, other preliminary clinical research shows that patients with similar injuries taking creatine 10 grams twice daily for 6 days, followed by 5 grams daily, do not have significant improvements in wrist muscle or hand function (46660).
• Spinal muscular atrophy. It is unclear if oral creatine is beneficial in patients with spinal muscular atrophy. Details: Preliminary clinical research shows that children with type II or III spinal muscular atrophy do not benefit from taking creatine orally for 6 months (46841). Doses were 2 grams daily for children aged 2-5 years, and 5 grams daily for children aged 5-18 years.
• Traumatic brain injury (TBI). It is unclear if oral creatine is beneficial in children with a TBI. Details: In children and adolescents who have suffered a TBI, preliminary clinical research shows that taking creatine orally 0.4 grams/kg daily for 6 months reduces the duration of post-traumatic amnesia by 60 days. It also reduces the risk of headache by 88%, fatigue by 87%, and dizziness by 80% when compared with control. There is also a trend towards reduced duration of intubation and total time in the intensive care unit or hospital (46694). More evidence is needed to rate creatine for these uses.

(Read more about CREATINE)

LIKELY SAFE ...when used orally and appropriately. Acetyl-L-carnitine has been used safely in doses up to 3 grams daily in clinical trials lasting up to 33 months (42,1589,1594,1595,1596,1597,1598,1599,3600,3601) (9105,9791,10076,12743,12745,58375,90755,90756,90759,90761)(90766,90767,90768,95063,95067,111862).

POSSIBLY SAFE ...when used parenterally and appropriately under medical supervision (1591,1592,12743).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Acetyl-L-carnitine has been safely used orally in children for up to 6 weeks (90754).

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

(Read more about ACETYL-L-CARNITINE)

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. Choline is safe in adults when taken in doses below the tolerable upper intake level (UL) of 3.5 grams daily (3094) ...when used intravenously and appropriately. Intravenous choline 1-4 grams daily for up to 24 weeks has been used with apparent safety (5173,5174).

POSSIBLY UNSAFE ...when used orally in doses above the tolerable upper intake level (UL) of 3. 5 grams daily. Higher doses can increase the risk of adverse effects (3094).

CHILDREN: LIKELY SAFE
when used orally and appropriately (3094). Choline is safe in children when taken in doses below the tolerable upper intake level (UL), which is 1 gram daily for children 1-8 years of age, 2 grams daily for children 9-13 years of age, and 3 grams daily for children 14-18 years of age (3094).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL. High doses can increase the risk of adverse effects (3094).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Choline is safe when taken in doses below the tolerable upper intake level (UL), which is 3 grams daily during pregnancy and lactation in those up to 18 years of age and 3.5 grams daily for those 19 years and older (3094,92114). There is insufficient reliable information available about the safety of choline used in higher doses during pregnancy and lactation.

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LIKELY SAFE ...when used orally and appropriately, short-term. Creatine supplementation appears to be safe when used at loading doses of up to 25 grams daily or 0.3 grams/kg daily for up to 14 days in healthy adults (1367,2100,2101,3996,4569,10064,15354,15520,46570,46587)(46673,46688,46719,46753,46801,103278,103279,108336). Creatine supplementation also appears to be safe when used at maintenance doses of 4-5 grams daily for up to 18 months (2101,4578,15353,15354,15520,46587,46673,46690,46753,46838,102164,103278,108336).

POSSIBLY SAFE ...when used orally and appropriately, long-term. Creatine supplementation has been safely used at doses of up to 10 grams daily for up to 5 years in some preliminary clinical research (1367,3996). There is insufficient reliable information available about the safety of creatine when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Creatine supplementation appears to be safe when used in appropriate doses in infants and children. Creatine 3-5 grams daily for 2-6 months has been safely used in children 5-18 years of age (6182,46596,46739,46841). Creatine 2 grams daily for 6 months has been safely used in children 2-5 years of age (46841). Additionally, weight-based dosing of creatine 0.1-0.4 grams/kg daily in infants and children or 4.69 grams/m2 in children weighing over 40 kg has been used safely for up to 6 months (46623,46629,46694,46759,104672).

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

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ACENOCOUMAROL (Sintrom) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the anticoagulant effects of acenocoumarol.  Details L-carnitine, the parent compound of acetyl-L-carnitine, might enhance the anticoagulant effects of acenocoumarol, an oral anticoagulant that is similar to warfarin, but shorter-acting (9878,12165). There are at least two case reports of INR elevation when L-carnitine was taken with acenocoumarol. 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). It is unclear if such an interaction would also occur with acetyl-L-carnitine.

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders, when taken with serotonergic drugs.  Details Animal research shows that acetyl-L-carnitine can increase levels of serotonin in the brain (95065).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, acetyl-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). It is unclear if such an interaction would occur with acetyl-L-carnitine.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the anticoagulant effects of warfarin.  Details L-carnitine, the parent compound of acetyl-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 acetyl-L-carnitine and warfarin.

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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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ATROPINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, choline might decrease the effects of atropine in the brain.  Details Animal research shows that administering choline one hour before administering atropine can attenuate atropine-induced decreases in brain levels of acetylcholine (42240). Theoretically, concomitant use of choline and atropine may decrease the effects of atropine.

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General ...Orally, acetyl-L-carnitine is generally well tolerated.
Most Common Adverse Effects:
Orally: Agitation, dry mouth, headache, insomnia, and reduced appetite. A metabolite of acetyl-L-carnitine has been reported to cause a fishy odor of the urine, breath, and sweat.

Cardiovascular ...Orally, one patient in a pharmacokinetic study reported high blood pressure 8 hoursafter taking acetyl-L-carnitine 500 mg; however, it is unclear if this was due to acetyl-L-carnitine or another factor (95061).

Dermatologic ...Orally, a combination of acetyl-L-carnitine and alpha-lipoic acid may cause rash (90441).

Gastrointestinal ...Orally, acetyl-L-carnitine may cause nausea, vomiting, diarrhea, constipation, hiccups, abdominal distension and gastrointestinal upset or pain. However, gastrointestinal symptoms do not usually occur more often in patients receiving acetyl-L-carnitine than in patients receiving placebo (1596,1599,12743,13007,58922,90755,95063,95067,111889,111894). Acetyl-L-carnitine may also cause dry mouth and anorexia (58342). When taken orally, a combination of acetyl-L-carnitine and alpha-lipoic acid may cause diarrhea, constipation, and dyspepsia (90441).

Neurologic/CNS ...Orally, acetyl-L-carnitine may cause headache and insomnia (90760,90767,95063). In one clinical trial, two patients with antiretroviral toxic neuropathy reported paresthesia, pain, and neuropathy after taking acetyl-L-carnitine 1000 mg daily (58342). A case of mania has been reported for a patient with bipolar I disorder currently in remission. The patient presented with symptoms after taking multiple supplements for the past 4 weeks including acetyl-L-carnitine 1000 mg twice daily. The symptoms appeared 3 days after beginning to take acetyl-L-carnitine and worsened over the next week. The patient had increased speech rate and volume and reported increased energy levels and racing thoughts. The patient's parent reported irritability and an increase in loud behaviors at home, similar to a previous episode of mania. The patient was advised to discontinue acetyl-L-carnitine, and the manic symptoms disappeared 3 days later (95062).

Psychiatric ...Orally, acetyl-L-carnitine may cause agitation (restlessness and motor overactivity) (1596,1599,12743,13007). Side effects reported in people with Alzheimer disease include psychiatric disturbances such as depression, mania, confusion and aggression, but it is not clear whether these are due to acetyl-L-carnitine or the condition itself (1594,1595,1596,1597,1598,1599,9105,10391).

Other ...One of the metabolites of acetyl-L-carnitine can cause the urine, breath, and sweat to have a fishy odor (12756). Also, foul smelling urine has been reported following oral use of a combination of acetyl-L-carnitine and alpha-lipoic acid (90441).

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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, choline is well tolerated when used appropriately. Adverse effects have been reported with doses exceeding the tolerable upper intake level (UL) of 3.5 grams daily.
Most Common Adverse Effects:
Orally: Fishy body odor. At high doses of at least 9 grams daily, choline has been reported to cause diarrhea, nausea, salivation, sweating, and vomiting.

Cardiovascular ...Orally, doses of choline greater than 7. 5 grams daily may cause low blood pressure (94648).

Gastrointestinal ...Orally, large doses of choline can cause nausea, vomiting, salivation, and anorexia (42275,91231). Gastrointestinal discomfort has reportedly occurred with doses of 9 grams daily, while gastroenteritis has reportedly occurred with doses of 32 grams daily (42291,42310). Doses of lecithin 100 grams standardized to 3.5% choline have reportedly caused diarrhea and fecal incontinence (42312).

Genitourinary ...Orally, large doses of choline greater than 9 grams daily have been reported to cause urinary incontinence (42291).

Neurologic/CNS ...Orally, high intake of choline may cause sweating due to peripheral cholinergic effects (42275).

Oncologic ...In one population study, consuming large amounts of choline was associated with an increased risk of colorectal cancer in females, even after adjusting for red meat intake (14845). However, more research is needed to confirm this finding.

Psychiatric ...Orally, large doses of choline (9 grams daily) have been associated with onset of depression in patients taking neuroleptics. Further research is needed to clarify this finding (42270).

Other ...Orally, choline intake may cause a fishy body odor due to intestinal metabolism of choline to trimethylamine (42285,42275,42310,92111,92112).

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General ...Orally, creatine is generally well-tolerated. Topically, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dehydration, diarrhea, gastrointestinal upset, muscle cramps, and water retention.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about interstitial nephritis, renal insufficiency, rhabdomyolysis, and venous thrombosis.

Cardiovascular ...Some research suggests that creatine supplementation can cause edema. In a randomized controlled trial, 26% of patients with amyotrophic lateral sclerosis (ALS) receiving creatine 10 grams daily reported edema after 2 months of treatment compared to 9% with placebo. The difference between groups was statistically significant at 2 months but not at month 4 and beyond. Creatine is believed to cause slight water retention, which may have been more apparent in patients who were immobilized due to ALS (46647). While this adverse drug reaction did not lead to worsening cardiac function in these patients, theoretically, creatine-related water retention could worsen congestive heart failure or hypertension.
There is one case report of lone atrial fibrillation in a 30-year-old male vegetarian. He started powdered creatine 20 grams daily for 5 days, followed by 2.5 grams daily for a month. However, he discontinued powdered creatine due to severe cramping and diarrhea, and reinitiated creatine supplementation a month later with an encapsulated formulation. Aside from gelatin in the capsule, creatine was the only ingredient listed in both formulations. During the loading dose phase, the patient developed dyspnea and palpitations and was diagnosed with lone atrial fibrillation in the emergency department. Symptoms resolved with treatment and supplement discontinuation (13187). Theoretically, alterations in electrolyte balance due to dehydration or diarrhea could lead to conduction abnormalities and arrhythmia; however, in this case, the patient had normal electrolyte levels. Contaminants in dietary supplements might also be responsible for adverse reactions; this specific creatine product was not tested for contaminants. It remains unclear whether creatine was associated with this event.
Theoretically, taking creatine nitrate might reduce blood pressure and heart rate due to its nitrate component. However, clinical research shows that creatine nitrate 12 grams daily for 7 days followed by 3 grams daily for 21 days does not lower blood pressure or heart rate acutely or chronically when compared to creatine monohydrate or placebo (95959).

Dermatologic ...In a small clinical trial of older, healthy males, one subject out of the 10 receiving creatine 5 grams four times daily for 10 days followed by 4 grams daily for 20 days reported a skin rash during the study. The type and severity of rash and whether it resolved after creatine was discontinued were not discussed (4572). Also, skin rash has been reported by patients taking celecoxib and creatine; however, whether this effect was due to creatine or celecoxib is unclear (46706).
Topically, burning, itching, redness, irritation, and perception of changes in skin temperature have been reported (104669).

Endocrine ...Creatine may influence insulin production (11330). In human research, insulin levels increased 120 and 240 minutes after creatine supplementation (46760); however, there was no effect in another trial (46732). In a clinical study, 0.3 grams/kg of creatine daily for one week significantly increased cortisol levels by 29%. However, the levels returned to baseline at week 2 (46615).

Gastrointestinal ...Some small clinical studies have reported diarrhea and vomiting with oral creatine supplementation (4584,11332,46562,46684,46698,46704,104673). Also, gastrointestinal distress, transient abdominal discomfort, constipation, heartburn, and nausea have been reported by a small number of individuals in randomized, controlled clinical trials (4572,11332,46527,46528,46573,46589,46622,46668,46684,46695), (46704,46771,95964,104668,104669,104673,108316). However, most high-quality clinical research shows that creatine does not increase the incidence of gastrointestinal upset (103102,103278,103279).
Undissolved creatine powder may cause gastroenteritis (1368). Additionally, simultaneous intake of creatine and caffeine powder may increase the occurrence of gastrointestinal distress (95964).

Hematologic ...There are two case reports of creatine-related venous thrombosis in otherwise healthy adults. In the first case, an active 18-year-old male who had been taking an unspecified dose of creatine daily for 3 months was diagnosed with venous thrombosis via MRI. The patient reported increased thirst and fluid consumption when taking creatine. In the second case, an active 31-year-old male who had recently taken a 5-hour flight was diagnosed with deep vein thrombosis. He had been taking an unspecified dose of creatine. After stopping creatine and receiving anticoagulation therapy for 6 months, both patients' thromboses were resolved and did not recur. Researchers speculate that dehydration might be to blame for these adverse events, as dehydration increases the risk of thrombosis. In both cases, thrombophilic conditions were ruled out, and a temporal relationship between creatine consumption and thrombosis was established (90301). However, it remains unclear if creatine was responsible for these thrombotic events.

Hepatic ...Despite two case reports describing hepatic injury in patients taking creatine (46701,90319), meta-analyses and clinical studies specifically evaluating the safety of creatine have not identified an increased risk for hepatic injury (103278,103279). In addition, population research suggests that there is not an association between creatine intake and liver fibrosis, cirrhosis, or hepatic steatosis. However, this study largely included subjects consuming less than 4 grams daily (112208).
One preliminary clinical trial specifically evaluated the effect of creatine loading and maintenance doses on hepatic function indices in healthy adults. No clinically significant changes in hepatic indices were reported in patients taking creatine loading doses of 20 grams daily for 5 days followed by maintenance doses of 3 grams daily for 8 weeks (46521). Another clinical study evaluated the impact of creatine monohydrate and creatine nitrate on liver function enzymes, showing no change in levels within 5 hours after the first dose of 12 grams or after continued consumption of 12 grams daily for 7 days followed by 3 grams daily for 21 days (95959). The patients that experienced hepatic injury in the available case reports were also taking other exercise supplements. Whether the reported adverse hepatic effects were due to creatine or the other supplements patients were taking is unclear. Also, neither of these case reports addressed whether the supplements were tested for contamination (46701,90319).

Musculoskeletal ...Creatine-associated increase in body mass is well documented in randomized, controlled clinical trials and is often as large as 1-2 kg during the five-day loading period of creatine (2101,4569,4589,4591,4600,4605,46504,46561,46815,46827)(46830,46843,95962,103279,112201). This may be considered an unwanted adverse reaction in some individuals and a desired effect of supplementation in others. This weight gain may interfere with mass-dependent activities such as running and swimming (46504,46823). Muscle cramping due to creatine supplementation has been reported in controlled clinical trials and may result from water retention in skeletal muscle (2104,4572,4584,30915,46562,46695,46826,46827,104673). However, most high quality clinical research shows that creatine does not increase the incidence of musculoskeletal injuries or muscle cramping (103102). In one case report, rhabdomyolysis in a weight lifter using creatine 25 grams daily over a one-year period has been reported (12820). Another case report describes an adult male who developed acute compartment syndrome of the leg after regular consumption of an unspecified amount of creatine and cocaine (112210).

Neurologic/CNS ...In clinical research, thirst, sleepiness, mild headache, and syncope have been reported for patients taking creatine, although the events were uncommon (46578,46615,46820). More serious adverse events have been reported for patients taking creatine in combination with other ingredients. A case of ischemic stroke has been reported for an athlete who consumed creatine monohydrate 6 grams, caffeine 400-600 mg, ephedra 40-60 mg, and a variety of other supplements daily for 6 weeks (1275). In another case, a 26 year old male reported with a hemorrhagic stroke linked to taking the supplement Jack3d, which contains creatine, DMAA, schizandrol A, caffeine, beta-alanine, and L-arginine alpha-ketoglutarate (90318). It is likely that these adverse events were due to other ingredients, such as caffeine, ephedra, and DMAA, which are known to have stimulant and vasoconstrictive properties.

Oncologic ...Population research shows that use of muscle building supplements such as creatine, protein, and androstenedione is associated with an increased odds of testicular germ cell cancer. This risk appears to be more apparent in early users, those using two or more muscle building supplements, and those with long-term use of the supplements. The odds of testicular germ cell cancer may be increased by up to 155% in males taking both creatine and protein supplements (90329). The risk of testicular germ cell cancer from creatine alone is unclear from this study.

Psychiatric ...Anxiety, irritability, depression, aggression, and nervousness have been reported in clinical research for patients taking creatine, although the effects are not common (46518). A case of acute organic psychosis was reported in a 32-year-old soldier in Iraq who was consuming excessive amounts of caffeine coupled with use of creatine (Creatamax, MaxiNutrition) one tablet twice daily for 3 weeks plus a specific stimulant containing bitter orange, guarana seed extract, and St. John's wort extract (Ripped Fuel Ephedra Free, Twinlabs) two tablets three times daily for 2 days prior to admission. The psychosis was considered likely due to caffeine consumption in combination with the stimulant supplement rather than creatine (37982).

Renal ...Isolated cases of renal dysfunction in patients taking creatine have been reported, including a case of interstitial nephritis in a healthy male (184) and a case of renal insufficiency in a football player (46828). In contrast to these cases, several clinical studies and case reports have shown that creatine does not affect markers of renal function in healthy adults (2120,3996,4573,16535,46735,46749,46758,46779,46813,95959,103279). Doses studied included 5- to 7-day loading regimens of 12 to 21 grams daily (2120,46813), or maintenance doses of 3-10 grams daily for up to 2 years (16535,46712,46758,95959). In two additional studies, creatine supplementation 15.75 grams for 5 days followed by 4.25 grams daily for 20 days with carbohydrate and protein ingestion led to no change of renal stress markers (46844). Other clinical research has shown that ingestion of creatine up to 30 grams daily for 5 years is not associated with an increased incidence of renal dysfunction (103102).
Other case reports involve patients with pre-existing renal dysfunction. For example, in one case, a patient with a history of recurrent renal failure developed relapsing steroid-responsive nephritis syndrome after taking creatine (1368,2118). In another case, a patient with diabetic nephropathy who was taking creatine and metformin developed severe metabolic acidosis and acute renal failure. It is unclear if creatine contributed to this event, as metformin alone is known to cause metabolic acidosis (46738). These case reports have raised concern that individuals with pre-existing renal dysfunction may be at increased risk for renal injury with creatine supplementation. However, no prospective clinical trials have been conducted in this population to clarify this concern.
In addition, two cases of acute kidney injury and hypercalcemia have been reported in 16 year old males that took 1-4 servings of creatine for less than 4 weeks; however, the creatine product contained unlabeled, very high doses of vitamin D, which is the likely cause of these symptoms (109739).
In one survey, 13% of male collegiate athletes taking creatine reported dehydration (4584). The Association of Professional Team Physicians has warned that creatine may cause dehydration, heat-related illnesses, and electrolyte imbalances, and reduce blood volume. Mild transient dehydration resulting in an elevated serum creatinine was also reported in a single person in a clinical trial (104672). However, a study found that creatine supplementation during preseason football training had no effect on fluid or electrolyte status (46845). Additionally, most high quality clinical research shows that creatine does not increase dehydration (103102). A theoretical increase in risk of dehydration due to intracellular fluid shifts has led most creatine manufacturers to caution about adequate hydration with creatine supplementation (4576).

Other ...There have been reports of heat intolerance with oral creatine supplementation (46505). Increases in formaldehyde production have been reported with creatine use. A-24 year-old man taking supratherapeutic doses of creatine monophosphate in combination with an energy supplement developed malignant hyperthermia after undergoing anesthesia. His symptoms included tachycardia, hypertension, hypercarbia, and hyperthermia. Environmental factors are suspected to have played a role in the development of malignant hyperthermia, so whether this adverse event was due to creatine at all is unclear (46717).
In 1997, three collegiate wrestlers died after engaging in a rapid weight-loss program in order to qualify for competition (93628). Initially creatine supplementation was considered to have contributed to or caused these deaths (12820,93629); however, investigations by the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) did not confirm this belief (12820,93630). It appears that only one of the three wrestlers had been using creatine. Instead, the deaths were related to drastic, short-term weight loss in which the wrestlers wore rubber suits, avoided hydration, and performed workouts in rooms with temperatures up to 33 °C (1368,93631).

(Read more about CREATINE)