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L-carnitine

Scientific Name(s): L-3-hydroxytrimethylaminobutanoate., L-beta-hydroxy-γ-trimethyl-amino-butyric acid., Y-trimethyl-beta-acetyl-butyrobetaine.
Common Name(s): Acetyl-L-carnitine, ALC, ALCAR, Bicarnesine, Carnitor, L-carnitine, LC, Levocarnitine, Propionyl-L-carnitine, Vitamin BT

Medically reviewed by Drugs.com. Last updated on Jan 29, 2018.

Clinical Overview

Use

Carnitine has been commercially advertised to improve exercise performance, enhance a sense of well-being, and to aid weight loss; however, clinical trials have not consistently supported these uses. The US Food and Drug Administration (FDA) has approved oral and intravenous (IV) L-carnitine for the treatment of primary and secondary carnitine deficiency as a result of inborn errors of metabolism. IV L-carnitine is also approved for the treatment of carnitine deficiency resulting from dialysis in patients with end-stage renal disease. Administration of L-carnitine in combination with orlistat or sibutramine has been shown to improve anthropomorphic, glycemic, and insulin parameters compared with L-carnitine monotherapy in patients with type 2 diabetes mellitus. Some lipid parameters as well as diabetic peripheral neuropathy have improved in diabetic patients whose diet was supplemented with L-carnitine. Limited clinical data support L-carnitine as an effective therapy for improving sperm quality for men with oligoasthenozoospermia. Limited data support the use of propionyl-L-carnitine for treatment of intermittent claudication in patients with peripheral artery disease, and data do not support its use in the treatment of congestive heart failure. Higher doses of propionyl-L-carnitine may increase the risk of atherogenesis and cardiovascular disease (CVD). Data do not support use of acetyl-L-carnitine in patients with cerebral ischemia.

Limited clinical data exist supporting L-carnitine's use in the management of mitochondrial dysfunction related to aging and apoptosis, AIDS-related dementia complex, drug-induced anemia, bipolar depression, cachexia, cardiovascular disease, dyslipidemia, dysthymic disorder, fatigue, drug-induced hepatotoxicity, intermittent claudication, migraine prophylaxis, muscle cramps, and drug-induced peripheral neuropathy.

Dosing

Because it increases adenosine triphosphate (ATP) generation and cellular oxidative respiratory processes, L-carnitine is often given with an antioxidant such as alpha-lipoic acid.

AIDS-related dementia complex: An IV dose of acetyl-L-carnitine 3 g/day for 4 weeks.

Athletic performance: Limited data support the use of L-carnitine 3 or 4g in prolonged time to exhaustion.

Cachexia: Liquid L-carnitine 4 g/day for 12 weeks administered orally.

Cardiovascular disease, secondary prevention: Oral maintenance doses of L-carnitine 2 to 6 g/day for up to 12 months have been used in clinical studies; some trials used oral or IV loading doses of 6 or 9 g/day for 5 to 7 days.

Diabetes mellitus, type 2: L-carnitine 2 g once daily for 1 year as a combination therapy with either orlistat or sibutramine. Other treatment options include an IV dose of acetyl-L-carnitine 5 mg/kg bolus loading dose followed by 0.025, 0.1, or 1 mg/kg constant infusion.

Diabetic peripheral neuropathy: acetyl-L-carnitine 1 g, 3 times daily administered over 1 year in adults with type 1 and 2 diabetes.

Dyslipidemia: A combination therapy of L-carnitine 2 g once daily with orlistat in adults with type 2 diabetes. A regimen of 500 mg twice daily was given for 12 weeks for dyslipidemia in patients with coronary artery disease without comorbid diabetes, liver disease, or renal disease.

Dysthymic disorder: Oral acetyl-L-carnitine1 g, 3 times daily for 7 weeks in elderly patients.

Hepatotoxicity induced by interferon/ribavirin therapy: L-carnitine 2 g administered orally twice daily for 12 months.

Hepatotoxicity induced by tuberculosis regimen: Carnitine 1 g administered orally twice daily for 4 weeks.

Hepatotoxicity induced by valproic acid overdose: IV loading dose of L-carnitine 100 mg/kg; a maintenance dose of 50 mg/kg (to a maximum of 3 g/dose) administered every 8 hours may be used.

Infertility, male: Carnitine 2 g/day, L-carnitine 2 to 3 g/day, acetyl-L-carnitine 0.5 to 3 g/day for up to 26 weeks is recommended.

Intermittent claudication: Propionyl-L-carnitine (PLC) 2 g once daily in patients with peripheral artery disease, combined with exercise training and other strategies.

Migraine prophylaxis: L-carnitine 500 mg/day administered orally for 12 weeks.

Mitochondrialmyopathy: L-carnitine 3 g/day for 2 months.

Muscle cramps: L-carnitine 300 mg administered 3 to 4 times daily for 8 weeks in patients with cirrhosis.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. L-carnitine is assigned the pregnancy Category B by the US Food and Drug Association (FDA); L-carnitine supplementation in breast-feeding mothers has not been clinically studied.

Interactions

Blood carnitine concentrations may be decreased in children who are concomitantly taking the anticonvulsants carbamazepine, phenobarbital, phenytoin, or valproic acid. Children concomitantly taking pivampicillin and other pivalate-conjugated antibiotics may also have reduced blood carnitine concentration levels.

Adverse Reactions

Nausea, vomiting, abdominal cramps, diarrhea, and a "fishy" body odor can occur with doses of about 3 g/day. Less common adverse effects have included pruritic rash, muscle weakness in uremic patients, and seizures in patients with seizure disorders. In patients with cardiovascular disease, oral doses of L-carnitine more than 3 g/day have resulted in a higher risk of atherogenesis and CVD.

Toxicology

There have been no reports of toxicity from levocarnitine overdosage. Large doses of levocarnitine may cause diarrhea.

Source

L-carnitine is a naturally occurring, nonprotein amino acid that is biosynthesized in the liver and kidneys from the essential amino acids lysine and methionine. Biosynthesis also requires vitamin C, vitamin B6, niacin, and catalysis reaction enzymes. Carnitine can also be ingested through the diet. In healthy adults and children, the body synthesizes sufficient amounts of L-carnitine to meet daily needs, so supplementation is not necessary. Additionally, the kidneys efficiently conserve carnitine so that even a carnitine-poor diet has little impact on the body's total carnitine content. Omnivorous diets that include red meat, fish, poultry, and dairy products provide about 60 to 180 mg of carnitine/day; in general, the redder the meat, the higher the carnitine content. Vegan diets provide about 10 to 12 mg/day.1, 2, 3, 4 Although carnitine is found in all cells, the majority (greater than 95%) of the body's carnitine content is found in skeletal and cardiac muscles that utilize fatty acids as a dietary fuel.1, 3

History

The generic term "carnitine" originates from the Latin carnus (flesh), as the compound was originally isolated from meat, and refers to the group of carnitine derivatives: L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. Dextro- forms also exist; however, only the levo-isomers are biologically active in humans. In 1989, the US Food and Nutrition Board of the Institute of Medicine determined that carnitine was not an essential nutrient and has not established a recommended dietary allowance for the compound. Commercially, carnitine has been promoted to improve exercise performance, enhance a sense of well-being, and to aid weight loss.1

Oral and IV L-carnitine has been approved by the FDA for treatment of primary and secondary carnitine deficiency as a result of inborn errors of metabolism. IV L-carnitine is also approved for the treatment of carnitine deficiency resulting from end-stage renal disease.5

Chemistry

L-carnitine facilitates beta-oxidation of long-chain fatty acids by transporting them into the mitochondria to be oxidized, which produces energy. It also exports short- and medium-chain fatty acids as well as toxic compounds from the mitochondria that accumulate as a result of normal and abnormal metabolism.1, 2, 6 It also participates in metabolism of branched chain amino acids and stabilizes cellular membranes.2 Acetyl-L-carnitine acts as a partial direct cholinergic agonist;7 has demonstrated neuroprotective, antinociceptive, and neuronal regenerative effects including increased responsiveness to nerve growth factor;8 and has been shown to be a specific inhibitor of mitochondrial reactive oxygen species.9

The brain contains high concentrations of L-carnitine and acetyl-L-carnitine and provides acetyl moieties for the production of the neurotransmitter acetylcholine. Animal studies have shown that although both L-carnitine and acetyl-L-carnitine supplementation effectively increased plasma and brain carnitine levels, only acetyl-L-carnitine effectively decreased oxidative damage in the brain (ie, lipid peroxidation; oxidized nucleotides in the hippocampus, cortex, and white matter).5 L-carnitine has limited oral bioavailability (approximately 15%), exhibits minimal protein binding, and is primarily excreted by the kidneys unchanged.10 Acetyl-L-carnitine is more often used in research than L-carnitine because it is more effectively absorbed by the small intestine and more efficiently transported across the blood-brain barrier.1

Uses and Pharmacology

Aging/Apoptosis/Senescence

Cellular energy production decreases with age. Less efficient mitochondrial electron transport systems and lower ATP production lead to excess production of reactive oxygen and nitrogen, which further damage mitochondrial enzymes and mitochondrial DNA. Mitochondrial dysfunction may be the underlying event in aging, in which degeneration occurs in all cells, independent of a trigger.11, 12, 13, 14 Senescence is the process that stops cell proliferation in both differentiated cells as well as stem cells. It is believed to be triggered when particular cells experience potentially oncogenic (DNA damage or epigenome perturbation) stress; thus far, senescence appears to be irreversible. Many components of a senescent cell also directly or indirectly promote inflammation—a cause and/or major contributor to almost every major age-related degenerative and hyperplastic disease.11 In vitro, acetyl-L-carnitine has demonstrated inhibitory activity on markers of senescence (senescence associated beta-galactosidase) and aging (mitochondrial reactive oxygen species and 4-hydroxynonenal subunit expression) in bone marrow derived from mesenchymal stem cells.9

Animal studies

Biochemical and electron microscopic studies of brains from aged rats have demonstrated that acetyl-L-carnitine (ALC) can counter age-related decline in tissue and improve fatty acid utilization. However, it may also yield an increase in oxidative stress due to increased electron flow. Administering ALC in combination with an antioxidant, such as alpha-lipoic acid, has been shown to modulate the oxidative effect.12, 13 When administered in combination, ALC plus lipoic acid led to partial improvements in age-related declines related to mitochondrial membrane potential, oxygen consumption, as well as numerous cofactors, minerals and enzymes associated with mitochondrial function and cellular respiration. However, the improvement in mitochondrial membrane potential, a key indicator of mitochondrial function, was greater when ALC was administered alone.13, 15

Neuronal mitochondria examined in brains from older rats treated with ALC plus alpha-lipoic acid demonstrated significant improvement in mitochondrial structure scores (P = 0.02) and number of intact mitochondria (P < 0.001) compared with the brains from untreated older rats; posttreatment, mitochondrial ultrastructure patterns in the older rats were similar to those found in younger rats (both treated and untreated).13 These results were similar to those found in studies of hepatocellular mitochondrial activity in older and younger rats, in which the combination of ALC (weeks 1 through4) plus lipoic acid (weeks 3 through 4) improved age related increases in oxidative stress (P = 0.0001) as well as lessening the decline in mitochondrial metabolism (P = 0.02). Oxidative stress levels of treated old rats were not significantly different than those of untreated younger rats. Additionally, the 3-fold decline in ambulatory activity of older rats was significantly reduced (P = 0.03) in treated older rats compared with that of untreated older rats, indicating an improved physiological parameter of metabolic activity. Doses of ALC plus lipoic acid were approximately 0.75 and 0.075 g/kg/day, respectively, for older rats and 1.2 and 0.12 g/kg/day for younger rats.15

Clinical data

The aging process is the greatest risk factor for the development of Parkinson disease. Some of the CNS changes that occur with Parkinson disease are also found in normal aging tissue (ie, reduced dopamine, reduced glutathione, increased markers for oxidative stress, alpha synuclein, amyloid, mitochondrial DNA deletions). The ability of nutritional supplements, including acetyl-L-carnitine, to manage these aging risk factors is supported by gene expression via the antioxidant response element, Keap/Nrf2 pathway, and by a transcription coactivator that regulates gene expression for energy metabolism, mitochondrial biogenesis, and mitochondrial structural integrity – peroxisome proliferator-activated receptor gamma co-activator 1 alpha.12 A randomized, double-blind, placebo-controlled, 2-phase study was conducted to determine the efficacy of L-carnitine on physical and mental fatigue and cognitive function in 70 Sicilian centenarians living 100 to 106 years of age and randomized to receive oral L-carnitine 2 g/day or placebo for 6 months with an additional 6-month follow- up. Supplementation with L-carnitine resulted in improvements in total fat mass, total muscle mass, plasma total carnitine, plasma long-chain and short-chain acylcarnitines, total cholesterol, physical fatigue after a 6-minute walking test, mental fatigue, fatigue severity, activities of daily living assessment, and a mini–mental state exam. No difference was observed in urine carnitine levels between groups. L-carnitine was well tolerated; 1 patient withdrew from the treatment group due to the adverse effect of diarrhea.16

Antioxidant

Animal studies

Because supplementation with acetyl-L-carnitine has been shown to increase mitochondrial electron transport activity and production of ATP, events that likely increase oxidative stress,12 administration is often done in combination with an antioxidant (ie, lipoic acid).12, 13, 15

Clinical studies

A single-blind, randomized, placebo-controlled trial (N = 47) of Taiwanese patients with coronary artery disease and at least 50% stenosis of one major artery demonstrated improvements in biomarkers of oxidative stress as well as an increased number of antioxidant enzymes after 12 weeks of supplementation with L-carnitine 500 mg twice daily. These data build upon earlier clinical trials showing a protective effect from higher doses of L-carnitine (at least 2,000 mg/day) on cardiac metabolism and function in patients with myocardial ischemic conditions. No serious adverse events were observed.2

Cachexia

A prospective, multicenter, double-blind, randomized, controlled trial compared the effect of L-carnitine with placebo on cachexia in 72 patients with stage IV pancreatic cancer (CARPAN trial). Supplementation with 4 g/day of oral liquid L-carnitine increased carnitine serum plasma levels up to 60% of the basic value at week 6 compared with a slight decline observed in the placebo group. At 12 weeks, BMI, body cell mass, and body fat increased compared with baseline in the L-carnitine group; whereas the placebo group experienced a reduction in BMI. Compared with the placebo group, cognitive function, global health status, and GI symptoms improved in patients receiving L-carnitine. However, no differences were observed in fatigue, survival benefit, or length of hospital stay between groups. L-carnitine was well tolerated and adverse effects did not differ between groups.56

Cardiovascular

Clinical studies

A systematic review and meta-analysis of randomized controlled trials (RCTs) published through November 2013 evaluated various dosages of L-carnitine in the setting of myocardial infarction. Five trials (N = 3,108) met inclusion criteria; all trials were of good quality with low heterogeneity. Daily maintenance doses ranged from 2 to 6 g of oral L-carnitine and were administered for up to 12 months; 3 trials used oral or IV loading doses of 6 or 9 g/day over 5 to 7 days. No differences in all-cause mortality were observed among participants using the 4 daily oral maintenance doses (2, 3, 4, 6 g) or between those using the 2 and 6 g/day doses in studies reporting specific cardiovascular events (ie, unstable angina, heart failure, myocardial infarction). An insignificant trend among participants favored the 3 g/day dose.3

In combination with alpha-lipoic acid, administration of ALC significantly reduced arterial tone (P = 0.008) in adults at least 55 years of age with stable coronary artery disease in a double-blind, crossover trial (N = 36). However, only subgroups with systolic blood pressure (SBP) above the median (greater than 135 mm Hg) and those with metabolic syndrome experienced improvements in SBP after treatment (P = 0.01 for both). Adverse reactions that led to withdrawal of 2 patients (pruritic rash and nausea) resolved after discontinuing treatment.17

In a critical review, the effectiveness of ALC and PLC in the treatment of cardiovascular diseases was assessed. PLC was considered effective for the treatment of intermittent claudication in patients with peripheral artery disease, especially when combined with exercise, pulsed muscular compression therapy, and other strategies. The largest of the 9 clinical trials evaluating PLC for intermittent claudication was conducted in 485 patients who received oral PLC 2 g/day for 1 year; patients with severely limited baseline maximum walking distance (less than 250 m) improved significantly compared with the placebo group (87% vs 46%, respectively; P < 0.01). Effects of ALC or PLC for treatment of ischemic heart disease (myocardial ischemia) were not well established, potentially favoring preventative effects rather than treatment. Likewise, clinical data supporting the use of ALC in patients with cerebral ischemia or PLC for congestive heart failure are insufficient.18 A systematic review was conducted of 18 studies to evaluate the use of carnitine supplementation for improving walking performance in patients with intermittent claudication. Most trials demonstrated small to modest improvements in walking performance. Pain-free walking distance was improved from 74 to 157 m, 31 to 54 m, and 23 to 132 m in pre- and posttest, parallel RCTs, and crossover RCTs, respectively. Improvements in maximum walking distance were also demonstrated in each study design from 71 to 135 m, 9 to 86 m, and 104 m, respectively. The pre- and posttest trials used dosages of oral or IV PLC 300 to 2,000 mg/day for 10 to 90 days, whereas the parallel and crossover RCTs used mostly PLC but also L-carnitine at dosages of 600 to 3,000 mg/day for 21 days to 1 year and 300 to 6,000 mg/day over a range of 4 to 21 days, respectively. Results were mostly independent of the level or quality of evidence, with some data supporting IV administration over oral.19

In patients with CVD, higher oral doses of L-carnitine (more than 3 g/day) have increased the risk of atherogenesis and cardiovascular morbidities. A positive, linear, dose-dependent association was found between plasma L-carnitine levels and the risk of coronary and peripheral artery disease, as well as overall CVD risk in patients undergoing cardiac evaluation. A 2013 study found increased rates of all-cause mortality and heart transplantation with higher levels of carnitine derivatives (acetyl- and palmitoyl-L-carnitine).3

Carnitine deficiency, primary and secondary

Although genetic disorders related to inborn errors of metabolism manifest as a wide range of symptoms that often start at or soon after birth, symptoms may not become apparent until adulthood. Faulty transport proteins or defects in enzymes lead to abnormalities in the synthesis and metabolism of proteins, carbohydrates, or fats and a buildup of toxic metabolites.20, 21, 22 L-carnitine is approved by the FDA for the treatment of primary systemic carnitine deficiency, and for secondary carnitine deficiency in short- and long-term treatment of patients with an inborn error of metabolism or with end-stage renal disease who are on dialysis. Two examples of inborn errors of metabolism include glutaryl coenzyme A dehydrogenase deficiency and fatty acid oxidation disorders. In the former, catabolism of l-lysine, L-hydroxylysine, and L-tryptophan are affected, which can lead to neurological disease if untreated; treatment includes a lysine-restricted diet plus supplementation with L-carnitine. The recommended dose for supplementation is oral L-carnitine 100 mg/kg/day initially, but later adjusted to maintain normal free L-carnitine levels, which is usually possible with 50 mg/kg/day in patients older than 6 years.21 Dietary fat restriction and L-carnitine supplementation were both noted as a treatment considerations for specific medium- and long-chain fatty acid disorders as well as mitochondrial trifunctional protein deficiency. However, clinical trials did not reveal major benefits from carnitine supplementation and potential adverse cardiac effects were a concern among health care providers surveyed.22 A Cochrane meta-analysis of carnitine supplementation for inborn errors of metabolism found no available RCTs or quasi-RCTs comparing carnitine with placebo in children or adults.20

Diabetes

Animal studies

The first report of PLC effects on insulin resistance was published in 2009 and noted in the fatty Zucker rat, an animal model of obesity and insulin resistance. Weight and food intake increased, and adiposity, serum insulin, insulin resistance model index, and triacylglycerol liver content improved in the rats receiving PLC.18 Supplementation with L-carnitine plus cholecalciferol in type 2 diabetic rats led to improved fasting plasma glucose compared with that of diabetic controls or with results of either agent administered alone (P < 0.001) in a randomized, controlled trial of 80 Sprague Dawley rats. The combination also improved fasting plasma insulin compared with that of diabetic control and L-carnitine groups (P < 0.001), as well as more improved insulin resistance than with either agent alone (P < 0.001).23

Clinical studies

The first report showing antidiabetic effects of ALC was published in 2000; dosage was 5 mg/kg IV bolus followed by 0.025, 0.1 or 1 mg/kg constant infusion versus placebo. Type 2 diabetic patients (N = 18) receiving ALC demonstrated higher tissue glucose uptake in a dose-dependent manner than the placebo group.18 A 2010 randomized, double-blind, controlled comparator study enrolled 258 obese white patients (body mass index [BMI] at least 30) with uncontrolled type 2 diabetes (glycosylated hemoglobin [HbA1c] greater than 8%); patients were treated with a variety of antidiabetic medications throughout the trial. Patients were randomized to receive orlistat (120 mg 3 times daily) with or without L-carnitine (2 g once daily) and were also placed on a diet and exercise plan. Improvements in body weight, BMI, HbA1c, fasting plasma glucose, low-density lipid (LDL)-cholesterol, and insulin resistance were significant in both groups; however, at 12 months, those in the L-carnitine plus orlistat group showed greater improvements than those receiving orlistat alone (P < 0.05 for each). No adverse events were reported.24 Another 2010 study with the same design was conducted in type 2 diabetic patients (N = 254) comparing sibutramine (10 mg/day) with and without L-carnitine (2 g/day) for 1 year. Although most parameters improved in both groups after 12 months, body weight, HbA1c, insulin resistance, fasting plasma insulin, and other parameters of insulin resistance (ie, retinol binding protein-4) improved significantly more with the addition of L-carnitine (P < 0.05 for each). However, improvements in triglycerides and the inflammatory marker, visfatin, were seen only in the L-carnitine plus sibutramine group (P < 0.05).25

A 2013 systematic review and meta-analysis evaluated randomized placebo-controlled trials to assess the metabolic effects of L-carnitine supplementation in type 2 diabetes mellitus. Four trials (N = 284) met inclusion criteria, with 1 administering 3 g/day while the other 3 trials administered 2 g/day. Although no significant effects were found on triglycerides, lipoprotein (a), HbA1c, or total cholesterol, oral supplementation with L-carnitine (2 or 3 g/day during a 12- to 52-week period) produced improvements in fasting plasma glucose (P = 0.002), LDL-cholesterol (P < 0.0001), apolipoprotein AI (P = 0.008), and apolipoprotein-B100 (P = 0.013). When the 3 g/day-study was excluded, the pooled effect for 2 g/day was no longer significant. Heterogeneity was not significant.26 Administration of IV L-carnitine 4 g/day for 7 days has also been shown to alleviate fasting-induced hunger and improve fasting-induced fatigue, cholesterol abnormalities (total and LDL-cholesterol), hepatic metabolic changes (AST, ALT, gamma glutamyltransferase), and weight loss in patients with metabolic syndrome in a small (N = 30) single-blind randomized, placebo-controlled pilot study.27

Dyslipidemias

Clinical studies

A 2010 randomized, double-blind, controlled comparator study enrolled 258 obese Caucasian patients (BMI ≥ 30) with uncontrolled type 2 diabetes (HbA1c > 8%); patients took a variety of antidiabetic medications throughout the trial. Patients were randomized to receive orlistat (120 mg 3 times daily) with or without L-carnitine (2 g once daily) and were also placed on a diet and exercise plan. Both groups showed significant improvements over the study period with regards to body weight, BMI, HbA1c, fasting plasma glucose, and insulin resistance; LDL-cholesterol was also significantly lower. However; at 12 months, results in the L-carnitine plus orlistat group were greater than with orlistat alone (P < 0.05 for each). No significant adverse events were reported.24

Hypertriglyceridemia is highly prevalent in Lebanese men (52%) of low to moderate socioeconomic status, which is associated with a diet high in cereals and low in animal products. In a 12-week, randomized, placebo-controlled trial (N = 85), adult Lebanese males of low socioeconomic status with hypertriglyceridemia (TG > 150 mg/dL) were given lysine (1 g/day), vitamin B6 (50 mg/day), lysine plus vitamin B6, or carnitine (1 g/day) supplements to determine effects on glycemia and lipids. While vitamin B6 supplementation was associated with improvements in total and high-density lipoprotein (HDL) cholesterol, no changes were observed in the carnitine or lysine groups.28

A meta-analysis was conducted on data from 12 RCTs to determine the effects of L-carnitine supplementation on the lipid profile in hemodialysis patients (N = 391). The majority of studies were of low quality. Total L-carnitine dosages ranged from 1.5 g/week to 3 g/day for a duration of approximately 12 weeks to 6 years. Based on data from the 8 trials reporting LDL-cholesterol, L-carnitine supplementation was associated with an improvement in LDL-cholesterol, especially in studies longer than 16 weeks using IV administration. However, no effects were found on triglycerides, total, HDL-, or very low density lipoprotein -cholesterol. Subgroup analysis based on geographic location indicated no differences in each of the countries studied.29

Administration of L-carnitine (500 mg twice daily) for 12 weeks significantly improved HDL-cholesterol (mean, +0.18 mmol/L; P=0.03) and apoliprotein-A1 (mean, +0.12 g/L; P=0.02) as well as antioxidant enzyme activity compared to changes seen with placebo in a single-blind, randomized, parallel, placebo-controlled study (n=47) conducted in patients with coronary artery disease. Exclusions included but were not limited to patients with diabetes, liver or renal disease, or those on high-dose statins. No significant changes were observed for triglycerides (TG), total cholesterol, LDL-cholesterol, or apolipoprotein-B (apo-B). Significant negative correlations were found between the L-carnitine levels and TG, as well as between superoxide dismutase activity and TG, total cholesterol, and apo-B.64

Exercise performance/Intolerance/Fatigue

Clinical data

A double-blind, placebo-controlled, dose-response, crossover study evaluated the short-term effects of a dose of L-carnitine 3 and 4 g on endurance performance in 26 healthy male athletes. Significant differences were found in running speeds with the dose of L-carnitine 3 g and placebo at lactic acid levels between 2 to 4 mmol/L; significant differences were also found with the L-carnitine 4 g dose and placebo at lactic acid levels 3.5 and 4 mmol/L. The differences found in both supplemented groups indicate that L-carnitine 3 or 4 g taken before physical exercise prolongs exhaustion. Additionally, lactic acid and running speed heart rates were improved in both L-carnitine groups compared with placebo. The subjective perception of difficulty prior to each speed increase during the test also improved in both treatment groups.4

Fatigue, the most debilitating symptom of multiple sclerosis (MS), is reported in up to 40% of patients. A 2012 Cochrane intervention review identified 2 RCTs evaluating L-carnitine in MS patients. In the only completed study at the time of the review, a crossover trial, 36 adults with relapsing-remitting and secondary progressive MS received acetyl-L-carnitine 2 g/day for 3 months and then amantadine 200 mg/day for 3 months after a 3-month wash-out period. Effects on MS-related fatigue were unclear. No serious adverse events were reported.30

Fatigue is also the most commonly reported symptom in cancer patients taking L-carnitine supplementation. Cancer-related fatigue is can be severely debilitating and is often not relieved with rest.31, 32 A 4-week, phase 3 trial randomly assigned L-carnitine 2 g/day or placebo to 367 cancer patients with invasive malignancies and fatigue; however, no statistically significant differences in adverse effects (ie, fatigue, depression, pain) between treatment and placebo groups, regardless of baseline carnitine levels.31 A 2015 Cochrane review and meta-analysis of treatments for fatigue in palliative care for patients with advanced diseases, including cancer, found limited evidence to support recommendations for any particular treatment. Evidence specifically related to L-carnitine was weak and inconclusive.32 The Society for Integrative Oncology clinical practice guidelines for the use of integrative therapies as supportive care in patients treated for breast cancer (2014) does not recommend the use of acetyl-L-carnitine for the treatment of fatigue due to lack of effect (moderate to high).33 In 2018, the American Society of Clinical Oncology (ASCO) endorsed the Society for Integrative Oncology (SIO) evidence-based guideline for the use of integrative therapies after breast cancer treatment, stating that acetyl-L-carnitine should not be recommended for improving fatigue during treatment (Grade D).68

Limited exercise capacity because of intermittent claudication is common in patients with peripheral artery disease; exercise-induced transient ischemia leads to an alteration in carnitine metabolism and results in depletion of carnitine levels and skeletal muscle energy supplies. A systematic review of data in18 studies evaluated the use of carnitine supplementation in improving walking performance in patients with intermittent claudication. Most trials demonstrated small to modest improvements in walking performance. Pain-free walking distance improved from 74 to 157 m, 31 to 54 m, and 23 to 132 m in pre- and posttest, parallel RCTs, and crossover RCTs, respectively. Maximum walking distance also improved in each study design from 71 to 135 m, 9 to 86 m, and 104 m, respectively. The pre- and post-test trials used dosages of 300 to 2,000 mg/day of oral or IV PLC, ranging from 10 to 90 days; the parallel and crossover RCTs used mostly PLC but also L-carnitine at dosages of 600 to 3,000 mg/day for 21 days to 1 year and 300 to 6,000 mg/day over a range of 4 to 21 days, respectively. Results were mostly independent of the level or quality of evidence, with some data supporting more benefit with IV administration compared than with oral.19 Consultants and an employee of Sigma-Tau (the manufacturer and principal developer of PLC) conducted a systematic review and meta-analysis of studies utilizing oral PLC to evaluate effects on walking performance in patients with intermittent claudication. In the primary analysis of the 6 Sigma-Tau phase 3 studies (N = 867), a net 16 m improvement in peak walking distance with 2 g/day PLC compared with placebo was reported, with similar results (net 45 meter improvement) in the meta-analysis that included an additional 7 RCTs (13 total studies; 1,854 total patients). Dosages ranged from 1 to 4 g/day (median 2 g/day) from 6 to 12 months and were well tolerated with no treatment-related differences between PLC intervention and placebo/comparator groups; incidence of death was 1.6% and 1.4%, respectively. The authors denied any industry, agency, and public funding sources.34 The American College of Cardiology Foundation/American Heart Association Guideline for the management of peripheral artery disease stated that the effectiveness of PLC in improving walking distance in patients with intermittent claudication is not well established (Level of Evidence: Limited).35

Exercise intolerance is also a prominent symptom in patients with mitochondrial myopathy (MM) and most often manifests as chronic progressive external ophthalmoplegia (CPOE; eyelid droop) associated with undue fatigue at relatively low exertion levels. A randomized, double-blind, placebo-controlled crossover trial of 12 patients with MM and CPOE plus 10 age- and gender-matched healthy controls documented improvements in exercise tolerance and oxygen consumption in MM patients receiving L-carnitine supplementation (3 g/day) compared with those receiving placebo. Patients with MM had lower mean peripheral muscle strength, height, body weight, and fat-free mass compared with that of controls.36

Hematological disorders

A prospective, randomized, open-label trial enrolled 69 adults with chronic hepatitis C to evaluate the effect of L-carnitine 4 g/day versus no treatment on drug-induced anemia; patients in both groups were treated with standard interferon-alfa plus ribavirin therapy. After 12 months, patients receiving L-carnitine experienced improvements in liver enzyme parameters (ie, AST, ALT), viremia, hemoglobin, and blood cell counts (ie, red blood cell, white blood cell, platelets). Improvement was also observed in the L-carnitine group for sustained virological response and relapse rate. No serious adverse events were noted in either group.57 In patients with renal dysfunction receiving maintenance hemodialysis, no differences were identified in hemoglobin, hematocrit, or erythropoietin between patients receiving acetyl-L-carnitine for at least 2 weeks or those receiving placebo in a systematic review and meta-analysis of 49 RCTs (N = 1,734).53

The KDIGO clinical practice guideline for anemia in chronic kidney disease (2012) does not recommend use of L-carnitine as adjuvant therapy due to insufficient evidence (very low).55

Hepatotoxicity

Overdose of valproic acid does not produce a readily identifiable toxidrome, but it may deplete hepatic L-carnitine stores, impairing mitochondrial transport via the carnitine shuttle. Therefore, L-carnitine has been considered a potential antidote to restore mitochondrial function, reduce production of toxic metabolites, and counter or reverse the toxic effects of valproic acid, although data are limited. A systematic review identified only 8 cases of acute exposure to valproic acid (7 monotherapy, 1 polydrug) in adults and children, plus 1 article that reported safety data from 674 patients. Intravenous administration was the preferred route because of the low oral bioavailability of L-carnitine; additionally, most overdose patients have been given activated charcoal that would render oral L-carnitine ineffective. Based on the data from these cases and toxicology references, the most commonly used loading dose was L-carnitine100 mg/kg; a maintenance dose of 50 mg/kg (to a maximum of 3 g/dose) administered every 8 hours was recommended to treat toxicity due to ongoing or delayed absorption of valproic acid. Although data were limited and publication bias was suspected, the authors considered L-carnitine administration reasonable for patients with acute overdose who demonstrated decreased levels of consciousness.10 There is also one case report of the use of L-carnitine to successfully treat PEG-asparaginase-induced hepatoxicity in a patient with acute lymphoblastic leukemia.58

A double-blind, randomized, placebo-controlled trial evaluated the potential benefit of adjunctive oral carnitine in preventing antituberculosis drug-induced hepatotoxicity (ATDH) in newly diagnosed, treatment-naive Iranian tuberculosis patients (N = 182). Carnitine deficiency was found to be more prevalent in tuberculosis (TB) patients than in healthy controls. All TB patients received first-line, anti-TB regimen per protocol (isoniazid, rifampin, ethambutol, pyrazinamide) and were randomly assigned to L-carnitine 2 g/day for 4 weeks or placebo. Of the 25% of patients who developed ATDH over the 2.5-year study period, 16.7% were in the L-carnitine group while 32.3% were in the placebo group (P = 0.049). Predisposing factors for ADTH based on multivariate logistic regression included patients older than age 35 years with diabetes mellitus, HIV infection, and placebo treatment.59

Infertility

Oxidative stress is thought to play an important role in male infertility, and it has been shown that mature, morphologically normal spermatozoa produce less reactive oxygen species (ROS) than do immature forms. Both enzymatic (eg, glutathione peroxidase, superoxide dismutase) and nonenzymatic (eg, carnitine, glutathione, carotenoids) antioxidant activity is found in abundance in the epididymis, seminal plasma, and spermatozoa. These oxidative and antioxidative processes are kept in balance under normal conditions, but excessive ROS results in extensive sperm dysfunction and DNA structural damage. Higher dietary intake of antioxidants, when compared with lower intake, has been shown to improve semen quality.37, 38 In women with endometriosis, ROS in follicular fluid may affect embryonic quality and development as well as the structure of the meiotic spindle of the oocyte, which is extremely sensitive to oxidative stress.39 A 2014 Cochrane systematic review and meta-analysis on antioxidants for use in male subfertility concluded that the only data for carnitines with low heterogeneity upon which an analysis could be made supported no association with carnitines (ie, acetyl-L-carnitine, acetyl-carnitine, L-carnitine) and beneficial sperm concentration at 6 months compared to placebo (2 trials, 116 men). Data were unsuitable to make a summation of effect on sperm motility.65

Experimental data

The potential protective effect of antioxidants, L-carnitine, and N-acetyl-cysteine (NAC) in preventing meiotic oocyte damage induced by follicular fluid from infertile women with mild endometriosis was explored in an experimental study. Follicular fluid (FF) samples were collected (N = 22) from women younger than 38 years of age with a BMI less than 30 who had either endometriosis-related infertility (n = 11, test group) or tubal or male factor-related infertility (n = 11, control). In vitro maturation of bovine oocytes in endometriosis FF produced a lower percentage of meiotically normal oocytes (presence of normal cell spindle in metaphase II) compared the percentage produced by oocytes matured in no FF or control FF. When assessing the effect of antioxidants alone or in combination with L-carnitine 0.6 mg/mL on endometriosis-FF–matured oocytes, a higher percentage of normal oocytes was produced with L-carnitine compared with those produced with no supplementation (80.61% vs 51.35%, respectively), which was similar to the no-FF group (86.36%) and control-FF (83.52%). NAC supplementation (1.5 mmol/L) and the combination of L-carnitine plus NAC produced slightly lower percentages of normal maturation (62.22% and 61.40%, respectively) than with L-carnitine alone.39

Animal data

In an experimental study evaluating the protective effects of L-carnitine against cyclophosphamide-induced infertility, male rats received IP cyclophosphamide (CP) 35 mg/kg, CP plus L-carnitine 21 mL/kg/day, or saline solution (control). After 3 weeks of treatment, rats given L-carnitine experienced increases in sperm motility, viability, and testosterone levels compared with the CP group. Apoptotic cells of the testis also decreased in the L-carnitine group compared with the CP group. Immunohistochemistry revealed nearly normal seminiferous tubules with the quality of spermatogenic cells improved with L-carnitine supplementation.40

Clinical data

A systematic review of 17 randomized trials (N = 1,665 men) assessed the effects of oral antioxidants, including carnitine, on sperm quality in infertile men and pregnancy rates in partners; heterogeneity in clinical methods prevented a meta-analysis from being performed. Over 50% of studies used a combination of antioxidants (vitamin C and E, zinc, selenium, folic acid, carnitine, N-acetyl-cysteine, astaxanthin); monotherapy with carnitine was most frequently studied, with 4 studies that enrolling 365 patients with asthenozoospermia or oligoasthenozoospermia. Although some benefit has been reported, clinical data are lacking. Supplementation with carnitine 2 g/day, L-carnitine 2 to 3 g/day, and/or acetyl-L-carnitine 0.5 to 3 g/day for up to 26 weeks resulted in improvements in sperm motility in 3 studies, improved pregnancy rates in 2 studies, and improved sperm concentration and morphology in 1 study.41 A randomized, double-blind, controlled trial (N = 52) in Iran compared the effects of L-carnitine with clomiphene citrate, an anti-estrogen commonly prescribed for male infertility, on idiopathic male infertility. Patients received either clomiphene citrate 25 mg/day or L-carnitine 2 g/day for 3 months. Compared with baseline, semen volume, sperm count, and motility improved with L-carnitine. Compared with clomiphene citrate, L-carnitine resulted in increased semen volume and equal improvements in sperm motility, but not sperm morphology.38 L-carnitine 1 g/day was used as a positive control in a 12-week, RCT that evaluated the effects phosphodiesterase-5 inhibitors on Leydig cell secretory function in men with oligoasthenospermia (N = 75). Although mean sperm concentration, percent motile spermatozoa, percent morphologically normal spermatozoa, and insulin-like 3 peptide levels were improved after treatment with vardenafil or sildenafil, no differences were seen with the positive control (L-carnitine) or negative control (untreated infertile men with oligoasthenospermia).37

Migraine prophylaxis

Because mitochondrial phosphorylation potential was reduced between headaches in migrainous patients, a single-blind, randomized, controlled clinical trial was conducted to investigate the effects of L-carnitine 500 mg/day and/or magnesium oxide 500 mg/day on migraine prophylaxis (N = 133). Conventional treatment and migraine elimination diet were continued throughout the study. After 12 weeks, L-carnitine supplementation produced the highest reductions in mean migraine days/month and the magnesium supplemented group produced the most improvements in the mean number of frequency, severity, and index. Overall, the effects of magnesium on all migraine indicators were more than those of L-carnitine, and the effects of routine treatments on all migraine indicators were more than those of the supplements.60

Muscle cramps

A prospective uncontrolled, nonrandomized study evaluated the effects of 2 doses of L-carnitine to reduce muscle cramps in cirrhosis patients; patients with ongoing symptoms of painful, involuntary contraction of skeletal muscles at rest or that woke them from sleep at least 3 times in the previous month were included. L-carnitine 300 mg 3 times daily (900 mg/day) or 4 times daily (1,200 mg/day) was provided for 8 weeks. Muscle cramp frequency and duration was assessed with questionnaires and severity was assessed by visual analog scale (VAS). Overall, 88.1% of patients experienced a reduction in cramping and 28.6% had complete elimination of cramps; mean VAS scores improved from 69.9 at baseline to 26.2 by the end of the study. A dose-response was observed, with 43.5% compared with 10.5% experiencing fewer cramps in the 1,200 mg/day and 900 mg/day groups, respectively. The higher dose also resulted in improved VAS scores (mean 9.9 vs 39.6, respectively). No adverse events were reported.61

Neurological

CNS

Animal data

Animal studies have demonstrated improved antioxidant activity of acetyl-L-carnitine over L-carnitine in the brain. Although L-carnitine and acetyl-L-carnitine both increased ambulatory activity, carnitine plasma levels, and brain levels in older rats, acetyl-L-carnitine provided greater improvements in biomarkers of oxidative damage (lipid peroxidation, hippocampal and cortical oxidized nucleotides, as well as hippocampal and white matter nitrotyrosine) in older rat brains compared with L-carnitine.6 The combination of acetyl-L-carnitine plus N-acetyl-cysteine also delayed degeneration of sensory neurons, reduced early retrograde death of spinal motor neurons, attenuated neuroinflammation, promoted axonal sprouting in injured cord segment, and produced an anti-apoptotic effect in segments rostral to injury sites.42

Clinical data

Neuronal loss and brain atrophy are hallmarks of AIDS-related dementia complex. Treatment strategies target the reduction of glutamate levels in the brain, which appears to be involved in the pathogenesis. In a small experimental study (N = 12) conducted in male AIDS patients with higher mean glutamate levels than those of controls, administration of IV acetyl-L-carnitine 3 g/day for 4 weeks reduced mean levels of glutamate compared with baseline (137 vs 246 micromol/L, respectively). A case of improved memory and attention after 12 weeks with acetyl-L-carnitine supplementation was also reported in a 37-year-old female AIDS patient admitted with abrupt onset of cognitive and motor symptoms associated with a fall in blood (201 to 41 micromol/l) and CSF (60 to 11 micromol/L) glutamate levels.43 A systematic review of 7 RCTs (N = 660) evaluated the effect of acetyl-L-carnitine in patients with hepatic encephalopathy. Administration of acetyl-L-carnitine 2 g/day was consistently associated with improvement in serum ammonia levels compared with those of placebo; however, heterogeneity was found among studies.44

The American Academy of Neurology (AAN) practice parameter for the management of dementia (2001) found the evidence to be incomplete or conflicting for the use of acetyl-L-carnitine as a cognitive-enhancing agent in patients with Alzheimer disease or mixed dementia.66

Because bipolar depression may also be associated with mitochondrial dysfunction, 40 patients with bipolar depression with incomplete responses to standard therapy were enrolled in a 12-week, double-blind, randomized, placebo-controlled, parallel-group, flexible-dose study of acetyl-L-carnitine (1 to 3 g/day) plus alpha-lipoic acid (0.6 to 1.8 g/day) as adjunctive therapy. Although supplementation reduced phosphocreatine levels in the parieto-occipital cortex, no differences were found between groups in depression scores compared with baseline in any outcome measure. Adverse effects were generally minor with diarrhea, foul-smelling urine, rash, constipation, and dyspepsia reported more frequently with supplementation than with placebo.45

The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder (MDD) in adults (2016) recommend acetyl-L-carnitine as third-line monotherapy for mild to moderate MDD (Level 2).67

In a double-blind, randomized clinical trial comparing the effect of oral ALC 1 g 3 times daily to fluoxetine 20 mg/day in 80 elderly patients with dysthymic disorder, ALC resulted in improved depression scores (Hamilton depression, Hamilton anxiety, Beck depression inventory) and attention performance scores. The latter did not reach significance in the fluoxetine group. ALC achieved a higher tolerance profile than that of fluoxetine.46

Peripheral

Animal data

Acetyl-L-carnitine has been shown to virtually eliminate sensory neuronal death and possibly improve regeneration after primary nerve repair. Enhanced regenerative capacity of neurons that survive peripheral nerve trauma has been demonstrated in animal studies. Rats treated with a 6-week regimen of 50 mg/kg/day acetyl-L-carnitine after unilateral sciatic nerve graft repairs were performed, increasing the total area of regenerating nerve fibers (2,242% increase) and Schwann cells (722% increase) in the grafts.47 Similarly, faster recovery of regenerated axons as well as increased number and diameter of resulting myelinated fibers were observed with supplementation of acetyl-L-carnitine in a rat sciatic nerve regeneration model.8

Clinical data

An analysis of 2 multicenter, double-blind, randomized, placebo-controlled trials evaluated the effects of 2 doses of acetyl-L-carnitine (1.5 and 3 g/day) administered over 1 year on clinical diabetic neuropathy in adults with type 1 and 2 diabetes (N = 1,346). Centers in the US and Canada (USC) participated in one study while those in the US, Europe, and Canada (USEC) participated in the second study. Demographic differences were evident among the 2 studies: weight and BMI were higher in the UCS group, while the UCES group included primarily white participants with a larger proportion of type 1 diabetic patients and a longer disease duration. Compared with the placebo group, sural nerve fiber numbers and regenerating clusters increased in patients receiving 1.5 g/day (500 mg 3 times daily) but not in the 3 g/day (1 g 3 times daily) group. Vibration perception improved in the fingers in both groups and in the toes of those receiving 3 g/day. Significantly greater reductions were also seen in UCS subgroups of patients younger than 55 years who had a BMI less than or equal to 30, type 2 diabetes, and HbA1c less than 8.5%. Mean clinical scores of both groups were improved compared with those of the placebo group, but not among groups. No differences were found in electrophysiological parameters. The greatest pain reduction was observed with 3 g/day after 1 year in type 2 diabetic patients with adequate drug compliance and HbA1c greater than 8.5%. Fewer patients taking 3 g/day reported pain, paresthesia, and hyperesthesia compared with those taking placebo; no other differences were observed in adverse events among groups.48 Data from the patients in these 2 studies was retrospectively examined to identify risk factors associated with sural nerve degeneration. Three risk groups were created based on the change in myelinated fiber density: "regenerators" (top 16 percentiles), "degenerators" (bottom 16 percentiles), and intermediate. Baseline HbA1c was the only factor that differed across the 3 groups with a mean of 8.3% (± 1.6%) for regenerators and 9.2 (± 1.8%) for degenerators.49

A systematic review was conducted to evaluate the potential use of nutraceuticals, including acetyl-L-carnitine, as adjuvant cancer therapy for treatment or prophylaxis of chemotherapy-induced peripheral neuropathy (CIPN). A total of 24 randomized, controlled, open-label, and retrospective trials were identified and results were equivocal. Insufficient data were available to recommend any of the 10 nutraceuticals reviewed. Acetyl-L-carnitine was reported as a possible treatment option for paclitaxel- and cisplatin-induced peripheral neuropathy based on data from 2 open-label studies, while a phase 3 trial demonstrated no positive prophylactic benefit. Adverse events were only reported for acetyl-L-carnitine and included mild nausea and insomnia.50 A negative effect of 3 g/day acetyl-L-carnitine was demonstrated at 24 weeks, but not at 12 weeks, on CIPN in women with a history of stage I to III breast cancer undergoing taxane-based treatment in a double-blind, randomized, placebo-controlled trial (N = 409). Grade 3 to 4 neuropathy was reported in 8 cases in the acetyl-L-carnitine group and 1 case in the placebo group (P = 0.46).51

The Society for Integrative Oncology clinical practice guidelines for the use of integrative therapies as supportive care in patients treated for breast cancer (2014) recommends against the use of acetyl-L-carnitine for the prevention of neuropathy in breast cancer patients due to adverse events (moderate to high).33 In 2018, the American Society of Clinical Oncology (ASCO) endorsed the Society for Integrative Oncology (SIO) evidence-based guideline for the use of integrative therapies after breast cancer treatment, stating that acetyl-L-carnitine is not recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer due to potential harm (Grade H).Lyman 2018 The ASCO clinical practice guidelines for prevention and management of CIPN in survivors of adult cancers (2014) strongly advised against the use of acetyl-L-carnitine for the prevention of CIPN in patients undergoing treatment with neurotoxic agents. An increase in incidence of CIPN has been documented at 24 weeks in a phase 3 trial in women with breast cancer receiving acetyl-L-carnitine versus placebo (high-quality evidence; strong recommendation). No recommendation could be made regarding use of acetyl-L-carnitine for treatment of CIPN based on inconclusive data (low-quality evidence, inconclusive).52

Renal disease

Clinical data

A systematic review and meta-analysis was conducted to confirm or refute previous data indicating the beneficial effect of L-carnitine on hemoglobin and erythropoietin dose in maintenance hemodialysis patients. A total of 49 RCTs (N = 1,734) comparing acetyl-L-carnitine with placebo or no treatment for at least 2 weeks were included; those that compared different doses, routes, or durations were excluded. Although LDL-cholesterol and C-reactive protein improved by L-carnitine supplementation, no significant differences were identified in any other lipid parameters, hemoglobin, hematocrit, albumin, or the required erythropoietin dose. The improvement in LDL-cholesterol was not considered to be clinically important. No adverse events were reported.53 Because approximately 95% of hemodialysis patients have been found to have carnitine deficiency, L-carnitine supplementation is used frequently as adjuvant therapy. However, because its use is controversial, another meta-analysis sought to assess the clinical benefit of L-carnitine on hemodialysis patients. The 25 eligible RCTs spanned more than 20 years, with sample sizes ranging from 10 to 113 patients (N = 1,172) and study durations ranging from 3 weeks to 36 months. Both oral and IV routes were used at doses ranging from 1 to 3 g/day and 10 to 20 mg/kg/hemodialysis treatment. L-carnitine supplementation was not associated with changes in any of the inflammation, oxidative stress, nutrition, anemia, dyslipidemia, or quality of life outcomes measured.54

The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for the anemia in chronic kidney disease (2012) does not recommend use of L-carnitine as adjuvant therapy due to insufficient evidence (very low).55

Dosing

Oral carnitine supplements are metabolized by microbiota prior to absorption; bioavailability of 1 to 6 g doses ranges from 5% to 18%. Certain gut microbiota species (eg, Gammaproteobacteria, Betaproteobacteria, and Firmicutes, including Acinetobacter species) can adversely affect the bioavailability of L-carnitine supplementation. The dynamics of skeletal muscle carnitine may also influence the metabolism of L-carnitine supplementation.3

Anemia, drug-induced

Improvements in hemoglobin, blood cell counts, viremia, and liver enzymes were achieved with supplemental L-carnitine 2 g twice a day for 12 months in a small study of patients with chronic hepatitis C treated with standard interferon-alfa plus ribavirin receiving.57

Cachexia

An oral liquid dose of L-carnitine 4 g/day for 12 weeks increased BMI, body cell mass, and body fat in patients with cachexia and stage IV pancreatic cancer (CARPAN trial).56

Cardiovascular disease, secondary prevention

L-carnitine 2 to 6 g/day oral maintenance doses for up to 12 months have been used in clinical studies with some trials administering oral or IV loading doses of 6 or 9 g/day for 5 to 7 days. An insignificant trend favored the 3 g/day dose in terms of all-cause mortality. Doses higher than 3 g/day oral L-carnitine are not recommended; higher doses of carnitine derivatives (acetyl- and palmitoyl-L-carnitine) have been shown to increase atherogenesis, CVD risk, all-cause mortality, and heart transplantations in patients with CVD.3 L-carnitine is often used in combination with an antioxidant, such as alpha-lipoic acid.

Carnitine deficiency, primary and secondary

L-carnitine is approved by the FDA for treatment of primary systemic carnitine deficiency, and for short- and long-term treatment of patients with an inborn error of metabolism or with end-stage renal disease on dialysis that results in a secondary carnitine deficiency. Maintenance doses for adults range from 1 to 3 g/day given as a once or twice daily divided dose. Refer to prescribing information for specific dosing recommendations.

Type 2 diabetes mellitus

Administration of L-carnitine 2 g once daily for 1 year to patients also receiving either orlistat or sibutramine demonstrated greater improvements in body weight, BMI, HbA1c, plasma glucose, LDL-cholesterol, and insulin resistance compared with antidiabetic medication alone.24, 25

Acetyl-L-carnitine also improved tissue glucose uptake as a 5 mg/kg IV bolus loading dose followed by 0.025, 0.1, or 1 mg/kg constant infusion in a small group of type 2 diabetic patients.18

Dyslipidemia

The addition of L-carnitine 2 g once daily to orlistat in adults with type 2 diabetes resulted in lower LDL-cholesterol than did either drug alone; however, other studies failed to find an effect on lipid parameters or triglycerides.24, 28, 29

Dysthymic disorder

Oral acetyl-L-carnitine 1 g 3 times daily administered for 7 weeks to patients over the age of 65 years with dysthymic disorder resulted in improved depression scores and attention performance.46

Fatigue

Limited data show use of a 3 or 4 g dose of L-carnitine prolonged time to exhaustion in 26 healthy male athletes.4

L-carnitine 3 g once daily for 2 months improved limits of tolerance, oxygen consumption, and constant work rate in a small group (N = 12) of patients with mitochondrial myopathy.30

Effects on multiple sclerosis-related fatigue are unclear.30

The Society for Integrative Oncology clinical practice guideline for the use of integrative therapies as supportive care in patients treated for breast cancer does not recommend the use of acetyl-L-carnitine for the treatment of fatigue.33

Hepatotoxicity, drug-induced

Data are limited on the use of L-carnitine as a valproic acid overdose antidote. A systematic review identified only 8 cases of acute exposure to valproic acid (7 monotherapy, 1 polydrug) in adults and children. Intravenous administration is the preferred route. A loading dose of L-carnitine 100 mg/kg was most commonly used; a maintenance dose of 50 mg/kg (to a maximum of 3 g/dose) administered every 8 hours was recommended to treat toxicity due to ongoing or delayed absorption of valproic acid.10

Carnitine deficiency was found to be more prevalent in TB patients than in healthy controls. Adjunctive administration of oral carnitine (1 g twice daily for 4 weeks) was used to reduce antituberculosis drug-induced hepatotoxicity resulting from first-line, anti-TB regimen (isoniazid, rifampin, ethambutol, pyrazinamide). 59

Infertility, male

Carnitine 2 g/day, L-carnitine 2 to 3 g/day, acetyl-L-carnitine 0.5 to 3 g/day for up to 26 weeks has been used successfully to improve sperm parameters and fertilization in men with oligoasthenozoospermia or asthenozoospermia.38, 41

Intermittent claudication, treatment

Propionyl-L-carnitine 2 g once daily is likely effective for treatment of intermittent claudication in patients with peripheral artery disease, especially when combined with exercise and other strategies. Administration for up to 1 year was most effective in patients with severely limited baseline maximum walking distance (less than 250 m).18 Dosages of propionyl-L-carnitine 300 mg/day to 2 g/day of PLC orally or IV ranging from 10 to 90 days, and L-carnitine at dosages of 300 mg/day to 6 g/day for 4 days to 1 year have improved walking distance, with some data supporting more benefit with IV administration compared with oral.19 The American College of Cardiology Foundation/American Heart Association guideline for the management of peripheral artery disease states that the effectiveness of propionyl-L-carnitine as a therapy to improve walking distance in patients with intermittent claudication is not well established.35

Migraine prophylaxis

Compared with magnesium, oral L-carnitine 500 mg/day for 12 weeks produced the highest reductions in mean migraine days/month. The magnesium-supplemented group experienced the most improvements in migraines for the mean number of frequency, severity, and index. Overall, the effects of magnesium on all migraine indicators were higher than those of L-carnitine, and the effects of routine treatments on all migraine indicators were higher than those of supplements.60

Muscle cramps

L-carnitine 300 mg 3 times daily (900 mg/day) or 4 times daily (1,200 mg/day) for 8 weeks was administered to patients with cirrhosis and ongoing symptoms of painful, involuntary contraction of skeletal muscles at rest or that woke them from sleep at least 3 times in the previous month. A dose-response was observed with 43.5% compared with 10.5% experiencing fewer cramps in the 1,200 and 900 mg/day groups, respectively. The higher dose also resulted in improved VAS scores (mean 9.9 vs 39.6, respectively).61

Neuropathy, central

Neuronal loss and brain atrophy are hallmarks of AIDS-related dementia complex. Administration of IV acetyl-L-carnitine 3 g/day for 4 weeks reduced mean levels of glutamate compared with baseline in a small experimental study (N = 12). A case report also documented improvement in memory and attention after 12 weeks of acetyl-L-carnitine supplementation in a 37-year-old female AIDS patient, subsequently diagnosed with AIDS dementia, who was admitted with abrupt onset of cognitive and motor symptoms associated with decreased blood (201 to 41 micromol/l) and CSF (60 to 11 micromol/L) glutamate levels.43

Acetyl-L-carnitine 1 to 3 g/day plus alpha-lipoic acid 0.6 to 1.8 g/day as adjunctive therapy for 12 weeks failed to improve depression scores compared with baseline in a small (N = 40) study of patients with bipolar depression.45

Neuropathy, peripheral

Acetyl-L-carnitine 1.5 and 3 g/day administered over 1 year to treat diabetic neuropathy in adults with type 1 and 2 diabetes (N = 1,346) increased in sural nerve fiber numbers and regenerated clusters in patients receiving 1.5 g/day (500 mg 3 times daily) but not in those receiving 3 g/day (1 g 3 times daily) compared with the placebo group. Vibration perception improved in the fingers in both treatment groups and in the toes of those receiving 3 g/day. Greater reductions were seen in the US-Canada subgroups of younger than 55 years and who had a BMI less than or equal to 30, type 2 diabetes, and HbA1c less than 8.5%. The greatest pain reduction was observed with 3 g/day after 1 year in type 2 diabetic patients with adequate drug compliance and HbA1c greater than 8.5%. Fewer patients taking 3 g/day reported pain, paresthesia, and hyperesthesia compared with those receiving placebo. Baseline HbA1c was the only factor that identified "regenerators" and "degenerators."48, 49

The Society for Integrative Oncology clinical practice guidelines for the use of integrative therapies as supportive care in patients treated for breast cancer do not recommend use of acetyl-L-carnitine for the prevention of neuropathy in breast cancer patients due to harm (moderate to high).33

The American Society of Clinical Oncology clinical practice guidelines for prevention and management of CIPN in survivors of adult cancers strongly advise against the use of acetyl-L-carnitine for the prevention of CIPN in patients undergoing treatment with neurotoxic agents. An increase in incidence of CIPN has been documented at 24 weeks in a phase 3 trial in women with breast cancer receiving acetyl-L-carnitine vs placebo (high-quality evidence; strong recommendation). No recommendation could be made regarding use of acetyl-L-carnitine for treatment of CIPN based on inconclusive data (low-quality evidence, inconclusive).52

Pregnancy / Lactation

Avoid use. L-carnitine is assigned the pregnancy Category B by the FDA; L-carnitine supplementation in breast-feeding mothers has not been clinically studied.

Reproductive studies have been performed in rats and rabbits at doses of up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to L-carnitine.

Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. In breast-feeding mothers receiving levocarnitine, any risks to the child need to be weighed against the benefits of levocarnitine supplementation to the mother.62 Discontinuation of levocarnitine in breast-feeding mothers should be considered.

Interactions

Carbamazepine, phenobarbital, phenytoin, and valproic acid may decrease blood concentrations of carnitine in children treated for convulsions.1, 63

Pivampicillin and other pivalate-conjugated antibiotics may decrease blood concentrations of carnitine and limit fatty acid oxidation.1

Adverse Reactions

Nausea, vomiting, abdominal cramps, diarrhea, and a "fishy" body odor can occur with doses of about 3 g/day. Less common adverse effects have included pruritic rash, muscle weakness in uremic patients, and seizures in patients with seizure disorders. Administering the daily dose in 3 divided doses may help reduce some adverse effects, such as nausea and vomiting.1, 2, 17 Some evidence suggests that intestinal bacteria metabolize carnitine to form trimethylamine-N-oxide, a substance that may increase cardiovascular risk, particularly in omnivores who consume meat versus in vegans or vegetarians.1

A systematic review of nutraceuticals used for chemotherapy-induced peripheral neuropathy identified 2 open-label studies and a phase 3 trial that investigated the use of acetyl-L-carnitine. Mild nausea (n = 2) and insomnia (n = 1) were reported in 2 trials (N = 52).39 In a fatigue treatment trial, adverse events including insomnia and nervousness led to withdrawal of 1 patient with multiple sclerosis who received acetyl-L-carnitine 1 g twice/day for 3 months.32

In patients with cardiovascular disease, higher oral doses of L-carnitine (more than 3 g/day) increased the risk of atherogenesis and CVD. A linear, dose-dependent association was found between plasma L-carnitine levels and risks of coronary and peripheral artery disease, as well as overall CVD risk in patients undergoing cardiac evaluation. A 2013 study also found increased rates of all-cause mortality and heart transplantation with higher levels of carnitine derivatives (acetyl- and palmitoyl-L-carnitine).3

Toxicology

The IV median lethal dose (LD50) of levocarnitine in rats is 5.4 g/kg, and the oral LD50 of levocarnitine in mice is 19.2 g/kg. There have been no reports of a levocarnitine overdosage; however, large doses may cause diarrhea.62

References

1. National Institutes of Health. Office of Dietary Supplements. Carnitine Fact Sheet for Health Professionals. Carnitine: What is it? https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/. Updated February 11, 2016. Accessed November 8, 2015.
2. Lee BJ, Lin JS, Lin YC, Lin PT. Effects of L-carnitine supplementation on oxidative stress and antioxidant enzymes activities in patients with coronary artery disease: a randomized, placebo-controlled trial. Nutr J. 2014;13:79.2509210810.1186/1475-2891-13-79
3. Shang R, Sun Z, Li H. Effective dosing of L-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2014;14:88.2504403710.1186/1471-2261-14-88
4. Orer GE, Guzel NA. The effects of acute L-carnitine supplementation on endurance performance of athletes. J Strength Cond Res. 2014;28(2):514-519.2426365910.1519/JSC.0b013e3182a76790
5. US Food and Drug Administration; Drugs@FDA. Levocarnitine. Accessed 19 December 2015 from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=CARNITOR.
6. Liu J, Head E, Kuratsune H, Cotman CW, Ames BN. Comparison of the effects of L-carnitine and acetyl-L-carnitine on carnitine levels, ambulatory activity, and oxidative stress biomarkers in the brain of old rats. Ann N Y Acad Sci. 2004;1033:117-131.15591009
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