Contents
L-Carnitine (β-hydroxy-γ-N-trimethylaminobutyric acid) is a derivative of the amino acid, lysine (Figure 1). It was first isolated from meat (carnus in Latin) in 1905. Only the L-isomer of carnitine is biologically active (1). L-Carnitine appeared to act as a vitamin in the mealworm (Tenebrio molitor) and was therefore termed vitamin BT(2). Vitamin BT, however, is a misnomer because humans and other higher organisms can synthesize L-carnitine (see Metabolism and Bioavailability). Under certain conditions, the demand for L-carnitine may exceed an individual's capacity to synthesize it, making it a conditionally essential nutrient (3, 4).
In healthy people, carnitine homeostasis is maintained through endogenous biosynthesis of L-carnitine, absorption of carnitine from dietary sources, and reabsorption of carnitine by the kidneys (5).
Humans can synthesize L-carnitine from the amino acids lysine and methionine in a multi-step process occurring across several cell compartments (cytosol, lysosomes, and mitochondria) (reviewed in 6). Across different organs, protein-bound lysine is methylated to form ε-N-trimethyllysine in a reaction catalyzed by specific lysine methyltransferases that use S-adenosyl-methionine (derived from methionine) as a methyl donor. ε-N-Trimethyllysine is released for carnitine synthesis by protein hydrolysis. Four enzymes are involved in endogenous L-carnitine biosynthesis (Figure 2). They are all ubiquitous except γ-butyrobetaine hydroxylase is absent from cardiac and skeletal muscle. This enzyme is, however, highly expressed in human liver, testes, and kidney (7).
L-carnitine is primarily synthesized in the liver and transported via the bloodstream to cardiac and skeletal muscle, which rely on L-carnitine for fatty acid oxidation yet cannot synthesize it (8). The rate of L-carnitine biosynthesis in humans was studied in strict vegetarians (i.e., in people who consume very little dietary carnitine) and estimated to be 1.2 µmol/kg of body weight/day (9). The rate of L-carnitine synthesis depends on the extent to which peptide-linked lysines are methylated and the rate of protein turnover. There is some indirect evidence to suggest that excess lysine in the diet may increase endogenous L-carnitine synthesis; however, changes in dietary carnitine intake level or in renal reabsorption do not appear to affect the rate of endogenous L-carnitine synthesis (6).
The bioavailability of L-carnitine from food can vary depending on dietary composition. For instance, one study reported that bioavailability of L-carnitine in individuals adapted to low-carnitine diets (i.e., vegetarians) was higher (66%-86%) than in those adapted to high-carnitine diets (i.e., regular red meat eaters; 54%-72%) (10). The remainder is degraded by colonic bacteria.
While bioavailability of L-carnitine from the diet is quite high (see Dietary L-carnitine), absorption from oral L-carnitine supplements is considerably lower. The bioavailability of L-carnitine from oral supplements (doses, 0.6 to 7 g) ranges between 5% and 25% of the total dose (5). Less is known regarding the metabolism of the acetylated form of L-carnitine, acetyl-L-carnitine (ALCAR); however, the bioavailability of ALCAR is thought to be higher than that of L-carnitine. The results of in vitro experiments suggested that ALCAR might be partially hydrolyzed upon intestinal absorption (11). In humans, administration of 2 g/day of ALCAR for 50 days increased plasma ALCAR concentrations by 43%, suggesting that either ALCAR was absorbed without prior hydrolysis or that L-carnitine was re-acetylated in the enterocytes (5).
L-Carnitine and short-chain acylcarnitine derivatives (esters of L-carnitine; see Figure 1) are excreted by the kidneys. Renal reabsorption of free L-carnitine is normally very efficient; in fact, an estimated 95% is thought to be reabsorbed by the kidneys (1). Therefore, carnitine excretion by the kidney is usually very low. However, several conditions can decrease the efficiency of carnitine reabsorption and, correspondingly, increase carnitine excretion. Such conditions include high-fat, low-carbohydrate diets; high-protein diets; pregnancy; and certain disease states (see Primary systemic carnitine deficiency) (12). In addition, when circulating L-carnitine concentration increases, as in the case of oral supplementation, renal reabsorption of L-carnitine may become saturated, resulting in increased urinary excretion of L-carnitine (5). Dietary or supplemental L-carnitine that is not absorbed by enterocytes is degraded by colonic bacteria to form two principal products, trimethylamine and γ-butyrobetaine. γ-Butyrobetaine is eliminated in the feces; trimethylamine is efficiently absorbed and metabolized to trimethylamine-N-oxide, which is excreted in the urine (13).
L-Carnitine is synthesized primarily in the liver but also in the kidneys and then transported to other tissues. It is most concentrated in tissues that use fatty acids as their primary fuel, such as skeletal and cardiac muscle. In this regard, L-carnitine plays an important role in energy production by conjugating to fatty acids for transport from the cytosol into the mitochondria (6).
L-Carnitine is required for mitochondrial β-oxidation of long-chain fatty acids for energy production (1). Long-chain fatty acids must be esterified to L-carnitine (acylcarnitine) in order to enter the mitochondrial matrix where β-oxidation occurs (Figure 3). On the outer mitochondrial membrane, CPTI (carnitine-palmitoyl transferase I) catalyzes the transfer of medium/long-chain fatty acids esterified to coenzyme A (CoA) to L-carnitine. This reaction is a rate-controlling step for the β-oxidation of fatty acid (13). A transport protein called CACT (carnitine-acylcarnitine translocase) facilitates the transport of acylcarnitine across the inner mitochondrial membrane. On the inner mitochondrial membrane, CPTII (carnitine-palmitoyl transferase II) catalyzes the transfer of fatty acids from L-carnitine to free CoA. Fatty acyl-CoA is then metabolized through β-oxidation in the mitochondrial matrix, ultimately yielding propionyl-CoA and acetyl-CoA (6). Carnitine is eventually recycled back to the cytosol (Figure 3).
Free (nonesterified) CoA is required as a cofactor for numerous cellular reactions. The flux through pathways that require nonesterified CoA, such as the oxidation of glucose, may be reduced if all the CoA available in a given cell compartment is esterified. Carnitine can increase the availability of nonesterified CoA for these other metabolic pathways (6). Within the mitochondrial matrix, CAT (carnitine acetyl transferase) catalyzes the transesterification of short- and medium-chain fatty acids from CoA to carnitine (Figure 3). The resulting acylcarnitine esters (e.g., acetylcarnitine) can remain in the mitochondrial matrix or be exported back into the cytosol via CACT. Free (nonesterified) CoA can then participate in other reactions, such as the generation of acetyl-CoA from pyruvate in a reaction catalyzed by pyruvate dehydrogenase (14). Acetyl-CoA can then be oxidized to produce energy (ATP) in the citric acid cycle.
In addition to its importance for energy production, L-carnitine was shown to display direct antioxidant properties in vitro (15). Age-related declines in mitochondrial function and increases in mitochondrial oxidant production are thought to be important contributors to the adverse effects of aging. Tissue L-carnitine concentrations have been found to decline with age in humans and animals (16). The expression of most proteins involved in the transport of carnitine (OCTN2) and the acylcarnitine shuttling system across the mitochondrial membrane (CPTIa, CPTII, and CAT; Figure 3) was also found to be much lower in the white blood cells of healthy older adults than of younger adults (17).
Preclinical studies in rodents showed that supplementation with high doses of acetyl-L-carnitine (ALCAR; Figure 1) reversed a number of age-related changes in liver mitochondrial function yet increased liver mitochondrial oxidant production (18). ALCAR supplementation in rats has also been found to improve or reverse age-related mitochondrial declines in skeletal and cardiac muscular function (19, 20). Co-supplementation of aged rats with L-carnitine and α-lipoic acid blunted age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in a variety of tissues (heart, skeletal muscle, and brain) (21-30). Co-supplementation for three months improved both the number of total and intact mitochondria and mitochondrial ultrastructure of neurons in the hippocampus (30). Although ALCAR exerts antioxidant activities in rodents, it is not known whether taking high doses of ALCAR will have similar effects in humans.
Nutritional carnitine deficiencies have not been identified in healthy people without metabolic disorders, suggesting that most people can synthesize enough L-carnitine (1). Even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources (9). Infants, particularly premature infants, are born with low stores of L-carnitine, which could put them at risk of deficiency given their rapid rate of growth. One study reported that infants fed carnitine-free, soy-based formulas grew normally and showed no signs of a clinically relevant carnitine deficiency; however, some biochemical measures related to lipid metabolism differed significantly from infants fed the same formula supplemented with L-carnitine (31). Soy-based infant formulas are now fortified with the amount of L-carnitine normally found in human milk (32).
Renal filtration maintains plasma concentrations of free carnitine around 40 to 50 micromoles (µmol)/L, while plasma concentrations of acetyl-L-carnitine (ALCAR; the most abundant carnitine ester) are around 3 to 6 µmol/L (8). Regardless of the etiology, plasma concentrations of free carnitine ≤20 µmol/L and increased acylcarnitine/free carnitine ratios (≥0.4) are considered abnormal (6). Low carnitine status is generally due to impaired mitochondrial energy metabolism or to carnitine not being efficiently reabsorbed by the kidneys. The rate of carnitine excretion is not a useful indicator of carnitine status because it can vary with dietary carnitine intake and other physiologic parameters. At present, there is no test that assesses functional carnitine deficiency in humans (6).
Primary systemic carnitine deficiency is a rare, autosomal recessive disorder caused by mutations (including deletions) in the SLC22A5 gene coding for carnitine transporter protein OCTN2 (organic cation transporter novel 2) (33). Individuals with defective carnitine transport have poor intestinal absorption of dietary L-carnitine, impaired L-carnitine reabsorption by the kidneys (i.e., increased urinary loss of L-carnitine), and defective L-carnitine uptake by muscles (4). The clinical presentation can vary widely depending on the type of mutation affecting SLC22A5 and the phenotypic manifestation of the mutation, i.e., age of onset, organ involvement, and severity of symptoms at the time of diagnosis (34). The disorder usually presents in early childhood and is characterized by episodes of hypoketotic hypoglycemia (that can cause encephalopathy), hepatomegaly, elevated liver enzymes (transaminases), and hypoammonemia in infants; progressive cardiomyopathy, elevated creatine kinase, and skeletal myopathy in childhood; or fatigability in adulthood (34, 35). The metabolic and myopathic symptoms in infants and children can be fatal such that treatment should start promptly to prevent irreversible organ damage (34). The diagnosis is established by demonstrating abnormally low plasma free carnitine concentrations, reduced carnitine transport of fibroblasts from skin biopsy, and molecular analysis of the gene coding for OCTN2 (33, 34). Treatment consists of pharmacological doses of L-carnitine that are meant to maintain a normal blood carnitine concentration, thereby preventing the risk of hypoglycemia and correcting metabolic and myopathic manifestations (34).
Secondary carnitine deficiency or depletion may result from either genetic or acquired conditions.
Hereditary causes include genetic defects in the metabolism of amino acids, cholesterol, and fatty acids, such as propionyl-CoA carboxylase deficiency (aka propionic acidemia) and medium chain acyl-CoA dehydrogenase deficiency (36). Such inherited disorders lead to a buildup of organic acids, which are subsequently removed from the body via urinary excretion of acylcarnitine esters. Increased urinary losses of carnitine can lead to the systemic depletion of carnitine (6).
Systemic carnitine depletion can also occur in disorders of impaired renal reabsorption. For instance, Fanconi's syndrome is a hereditary or acquired condition in which the proximal tubular reabsorption function of the kidneys is impaired (37). This malfunction consequently results in increased urinary losses of carnitine. Patients with renal disease who undergo hemodialysis are at risk for secondary carnitine deficiency because hemodialysis removes carnitine from the blood (see End-stage renal disease) (38).
One example of an exclusively acquired carnitine deficiency involves chronic use of pivalate-conjugated antibiotics. Pivalate is a branched-chain fatty acid anion that is metabolized to form an acyl-CoA ester, which is transesterified to carnitine and subsequently excreted in the urine as pivaloyl carnitine. Urinary losses of carnitine via this route can be 10-fold greater than the sum of daily carnitine intake and biosynthesis and lead to systemic carnitine depletion (see Drug interactions) (39).
Finally, a number of inherited mutations in genes involved in carnitine shuttling and fatty acid oxidation pathways do not systematically result in carnitine depletion (such that carnitine supplementation may not help mitigate the symptoms) but lead to abnormal profiles of acylcarnitine esters in blood (35, 40).
Endogenous biosynthesis of L-carnitine is catalyzed by the concerted action of four different enzymes (see Metabolism and Bioavailability) (Figure 2). This process requires two essential amino acids (lysine and methionine), iron (Fe2+), vitamin B6 in the form of pyridoxal 5’-phosphate, niacin in the form of nicotinamide adenine dinucleotide (NAD), and may also require vitamin C (ascorbate) (4). One of the earliest symptoms of vitamin C deficiency is fatigue, thought to be related to decreased synthesis of L-carnitine (41).
In most studies discussed below, it is important to note that treatment with L-carnitine or acyl-L-carnitine esters (i.e., acetyl-L-carnitine [ALCAR], propionyl-L-carnitine; Figure 1) was generally used as an adjunct to standard medical therapy, not in place of it. It is also important to consider the fact that the bioavailability of L-carnitine and acylcarnitine derivatives administered orally is low (~10-20%) (see Metabolism and Bioavailability). Intravenous administration is more likely to increase plasma carnitine concentration, yet homeostatic mechanisms tightly control blood concentration through metabolism and renal excretion: Up to 90% of 2 g of L-carnitine administered intravenously is excreted into the urine within 12 to 24 hours. Only a fraction of the dose is thought to enter the endogenous carnitine pool — largely found in skeletal muscle (reviewed in 8).
Several small clinical trials have explored whether supplemental L-carnitine could improve glucose tolerance in people with impaired glucose metabolism. A potential benefit of L-carnitine in these patients is based on the fact that it can (i) increase the oxidation of long-chain fatty acids which accumulation may contribute to insulin resistance in skeletal muscle, and (ii) enhance glucose utilization by reducing acyl-CoA concentration within the mitochondrial matrix (see Biological Activities) (42). A meta-analysis of five trials in participants with either impaired fasting glucose, type 2 diabetes mellitus, or nonalcoholic steatohepatitis found evidence of an improvement in insulin resistance with supplemental L-carnitine compared to placebo (43). Another meta-analysis of four randomized, placebo-controlled trials found evidence of a reduction in fasting plasma glucose concentration and no improvement of glycated hemoglobin concentration in subjects with type 2 diabetes mellitus supplemented with acetyl-L-carnitine (ALCAR) (44). A third meta-analysis of 16 trials suggested that supplementation with (acyl)-L-carnitine may reduce fasting blood glucose and glycated hemoglobin concentrations, but not resistance to insulin (45). In a recent double-blind, randomized, placebo-controlled trial, the effect of ALCAR was examined in 229 participants treated for type 2 diabetes mellitus, hypertension, and dyslipidemia (46). ALCAR supplementation (1 g/day for 6 months) had no effect on systolic or diastolic blood pressure, markers of kidney function (i.e., glomerular filtration rate and albuminuria), markers of glucose homeostasis (i.e., glucose disposal rate, glycated hemoglobin concentration, and a measure of insulin resistance), and blood lipid profile (i.e., concentrations of triglycerides, lipoprotein (a), LDL-cholesterol, HDL-cholesterol, and total cholesterol) (46).
In the studies discussed below it is important to note that treatment with L-carnitine or propionyl-L-carnitine was used as an adjunct (in addition) to appropriate medical therapy, not in place of it.
Myocardial infarction (MI) occurs when an atherosclerotic plaque in a coronary artery ruptures and obstructs the blood supply to the heart muscle, causing injury or damage to the heart (see the page on Heart Attack). Several clinical trials have explored whether L-carnitine administration immediately after MI diagnosis could reduce injury to heart muscle resulting from ischemia and improve clinical outcomes. An early trial in 160 men and women diagnosed with a recent MI showed that oral L-carnitine (4 g/day) in addition to standard pharmacological treatment for one year significantly reduced mortality and the occurrence of angina attacks compared to the control (47). In another controlled trial in 96 patients, treatment with intravenous L-carnitine (5 g bolus followed by 10 g/day for three days) following a MI resulted in lower concentrations of creatine kinase-MB and troponin-I, two markers of cardiac injury (48). However, not all clinical trials have found L-carnitine supplementation to be beneficial after MI. For example, in a randomized, double-blind, placebo-controlled trial in 60 participants diagnosed with an acute MI, neither mortality nor echocardiographic measures of cardiac function differed between patients treated with intravenous L-carnitine (6 g/day) for seven days followed by oral L-carnitine (3 g/day) for three months and those given a placebo (49). Another randomized placebo-controlled trial in 2,330 patients with acute MI, L-carnitine therapy (9 g/day intravenously for five days, then 4 g/day orally for six months) did not affect the risk of heart failure and death six months after MI (50).
A 2013 meta-analysis of randomized controlled trials found that L-carnitine therapy in patients who experienced an MI reduced the risks of all-cause mortality (-27%; 11 trials; 3,579 participants), ventricular arrhythmias (-65%; five trials; 229 participants), and angina attacks (-40%; 2 trials; 261 participants), but had no effect on the risks of having a subsequent myocardial infarction or developing heart failure (51). Because about 90% of oral L-carnitine supplements is unlikely to be absorbed, one could ask whether the efficacy is equivalent between protocols using both intravenous and oral administration and those using oral administration only (8). This has not been examined in subgroup analyses.
Heart failure is described as the heart's inability to pump enough blood for all of the body's needs (see the page on Heart Failure). In coronary heart disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent heart regions from getting adequate circulation, ultimately resulting in cardiac damage and impaired pumping ability. Myocardial infarction may also damage the heart muscle, which could potentially lead to heart failure. Further, the diminished heart’s capacity to pump blood in cases of dilated cardiomyopathy may lead to heart failure. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction (LVEF), an objective measure of the heart's pumping ability. An LVEF of less than 40% is indicative of systolic heart failure (52).
An abnormal acylcarnitine profile and a high acylcarnitine to free carnitine ratio in the blood of patients with heart failure have been linked to disease severity and poor prognosis (53-55). Addition of L-carnitine to standard medical therapy for heart failure has been evaluated in several clinical trials. A 2013 meta-analysis of 17 randomized, placebo-controlled studies in a total of 1,625 participants with heart failure found that oral L-carnitine (1.5-6 g/day for seven days to three years) significantly improved several measures of cardiac functional capacity (including exercise tolerance and markers of the left ventricle function), yet had no impact on all-cause mortality (56).
Angina pectoris is chest pain that occurs when the coronary blood supply is insufficient to meet the metabolic needs of the heart muscle (as with ischemic heart disease; see the page on Angina Pectoris) (57). In a prospective cohort study in over 4,000 participants with suspected angina pectoris, elevated concentrations of certain acylcarnitine intermediates in blood were associated with fatal and non-fatal acute myocardial infarction (58). In early studies, the addition of oral L-carnitine or propionyl-L-carnitine to pharmacologic therapy for chronic stable angina modestly improved exercise tolerance and decreased electrocardiographic signs of ischemia during exercise testing in some angina patients (59-61). Another early study examined hemodynamic and angiographic variables before, during, and after administering intravenous propionyl-L-carnitine (15 mg/kg body weight) in men with myocardial dysfunction and angina pectoris (62). In this study, propionyl-L-carnitine decreased myocardial ischemia, evidenced by significant reductions in ST-segment depression and left ventricular end-diastolic pressure (62). No recent and/or large-scale studies have been conducted to further examine the potential benefit of L-carnitine or propionyl-L-carnitine in the management of angina pectoris.
In peripheral arterial disease, atherosclerosis of the arteries that supply the lower extremities may diminish blood flow to the point that the metabolic needs of exercising muscles are not sufficiently met, thereby leading to ischemic leg or hip pain known as claudication (see the page on Intermittent Claudication in Peripheral Arterial Disease) (63). Several clinical trials have found that treatment with propionyl-L-carnitine improves exercise tolerance in some patients with intermittent claudication. In a double-blind, placebo-controlled, dose-titration study, 1 to 3 g/day of oral propionyl-L-carnitine for 24 weeks was well tolerated and improved maximal walking distance in patients with intermittent claudication (64). In a randomized, placebo-controlled study of 495 patients with intermittent claudication, 2 g/day of propionyl-L-carnitine for 12 months significantly increased maximal walking distance and the distance walked prior to the onset of claudication in patients whose initial maximal walking distance was less than 250 meters (m), but no effect was seen in patients who had an initial maximal walking distance greater than 250 m (65). More recent trials have associated oral propionyl-L-carnitine supplementation (2 g/day for several months) with improved walking distance and claudication onset time (66, 67), as well as with higher pain-free walking distance and higher ankle-brachial index (a diagnostic measure of peripheral arterial disease) (68). Two 2013 systematic reviews of interventions concluded that the modest benefit of propionyl-L-carnitine on walking performance was equivalent or superior to that obtained with drugs approved for claudication in the US (e.g., pentoxyphylline, cilostazol) yet inferior to improvements seen with supervised exercise interventions (69, 70).
L-Carnitine and short/medium-chain acylcarnitine molecules are removed from the circulation during hemodialysis. Both L-carnitine loss into the dialysate and impaired synthesis by the kidneys contribute to a progressive carnitine deficiency in patients with end-stage renal disease (ESRD) undergoing hemodialysis (71). The low clearance of long-chain acylcarnitine molecules leads to a high acylcarnitine-to-L-carnitine ratio that has been associated with a higher risk of cardiovascular mortality (72). Carnitine depletion in patients undergoing hemodialysis may lead to various conditions, such as muscle weakness and fatigue, plasma lipid abnormalities, and refractory anemia. A 2014 systematic review and meta-analysis of 31 randomized controlled trials in a total of 1,734 patients with ESRD found that L-carnitine treatment — administered either orally or intravenously — resulted in reductions of serum C-reactive protein (a marker of inflammation and predictor of mortality in patients undergoing hemodialysis) and LDL-cholesterol, although the latter was not deemed to be clinically relevant (73). There was no effect of L-carnitine on other serum lipids (i.e., total and HDL-cholesterol, triglycerides) and anemia-related indicators (i.e., hemoglobin concentration, hematocrit, albumin, and required dose of recombinant erythropoietin) (73).
The US National Kidney Foundation did not recommend routine administration of L-carnitine to subjects undergoing dialysis yet encouraged the development of trials in patients with select symptoms that do not respond to standard therapy, i.e., persistent muscle cramps or hypotension during dialysis, severe fatigue, skeletal muscle weakness or myopathy, cardiomyopathy, and anemia requiring large doses of erythropoietin (74, 75).
Finally, the use of L-carnitine (10-20 mg/kg body weight given as a slow bolus injection) is approved by the US FDA to treat L-carnitine deficiency in subjects with ESRD undergoing hemodialysis (76).
The use of certain antiretroviral agents (nucleoside analogs) has been associated with an increased risk of developing peripheral neuropathy in HIV-positive individuals (77, 78). Small, uncontrolled, open-label intervention studies have suggested a beneficial effect of acetyl-L-carnitine (ALCAR) in patients with painful neuropathies. An early uncontrolled study found that 10 out of 16 HIV-positive subjects with painful neuropathy reported improvement after three weeks of intravenous or intramuscular ALCAR treatment (79). Results from another uncontrolled intervention in 21 HIV-positive patients suggested that long-term (two to four years) oral ALCAR supplementation (1.5 g/day) may be a beneficial adjunct to antiretroviral therapy to improve neuropathic symptoms in some HIV-infected individuals (80, 81). Additionally, two small studies in participants presenting with antiretroviral-induced neuropathy found significant reduction in subjects' mean pain intensity with oral ALCAR (1-3 g/day) for 4 to 24 weeks, but no effect on objective neurophysiological parameters was found (82, 83).
A double-blind, placebo-controlled trial in 90 HIV-positive patients with symptomatic distal symmetrical polyneuropathy found no benefit of intramuscular injection with 1 g/day of ALCAR for two weeks in the intention-to-treat analysis, but there was some pain relief in the group of 66 patients who completed the trial (84). Large-scale, controlled studies are needed before any conclusions can be drawn.
Peripheral nerve dysfunction occurs in about 50% of people with diabetes mellitus, and chronic neuropathic pain is present in about one-third of people with diabetic peripheral neuropathy (85). Advanced stages of diabetic peripheral neuropathy can lead to recurrent foot ulcers and infections, and eventually amputations (86). A 2019 systematic review (87) identified three placebo-controlled interventions that examined the effect of oral supplementation with acetyl-L-carnitine (ALCAR; 1.5-3.0 g/day for one year) in individuals with diabetic peripheral neuropathy (3, 88). Low-quality evidence suggested a lower level of pain with ALCAR, as measured with a visual scale analog. Low-quality evidence from another trial that compared the effect of ALCAR (1.5 g/day) with that of methylcobalamin (1.5 mg/day) for 24 weeks suggested no difference between treatments regarding the extent of functional disability (using the Neuropathy Disability Scale) or measures of symptom quality and severity (using the Neuropathy Symptom Scale) (89).
A few randomized, double-blind, placebo-controlled trials have examined whether ALCAR might help prevent or treat chemotherapy-induced peripheral neuropathy. A trial in 150 participants with either ovarian cancer or castration-resistant prostate cancer found no evidence that ALCAR (1g every 3 days) given with the anticancer drug sagopilone (for up to six cycles of treatment) reduced the overall risk of peripheral neuropathy compared to a placebo (90). However, ALCAR reduced the risk of high-grade sagopilone-induced neuropathy (90). In contrast, another trial in 409 women with breast cancer found that ALCAR (3 g/day for 24 weeks) increased anticancer drug (taxanes)-induced peripheral neuropathy and decreased measures of functional status compared to placebo (91). A follow-up study reported that the negative impact of 24-week treatment with ALCAR was still observed at week 52; however, no differences between ALCAR and placebo were apparent at week 104 (92). Finally, one trial in 239 participants already suffering from chemotherapy-induced peripheral neuropathy reported a reduction in the severity of neuropathic symptoms with ALCAR (3 g/day for eight weeks) compared to placebo (93). Improvements in electrophysiological parameters were also observed with ALCAR treatment (93).
The results from these trials are conflicting and thus difficult to interpret. The efficacy of ALCAR in the prevention and treatment of chemotherapy-induced peripheral neuropathy remains to be established (94).
A 2018 meta-analysis identified 12 randomized controlled trials, including 791 participants, that examined the effect of ALCAR on symptoms of depression (95). Evidence from nine trials suggested a reduction in depressive symptoms with ALCAR (3 g/day for a median 8 weeks) compared to a placebo. Three trials that compared ALCAR treatment (1-3 g/day for 7-12 weeks) and antidepressant medications found ALCAR was as effective as antidepressants in treating depressive symptoms (95). Another meta-analysis of trials that compared the safety profile of antidepressants found evidence of fewer adverse effects, and consequently, better adherence to treatment with ALCAR compared to placebo and in contrast to classical pharmaceutical agents (96).
The metabolomic profiling of acylcarnitine molecules showed variations in serum concentrations of subjects along the continuum from cognitively healthy to affected by Alzheimer's disease (97). Changes in the blood concentrations of specific acylcarnitines in subjects with either subjective memory complaints, mild cognitive impairment, or Alzheimer's disease, compared to cognitively healthy peers may reflect changes in the transport of fatty acids into the mitochondria and/or impairments in energy production. Several clinical trials conducted in the 1990s examined the effect of acetyl-L-carnitine (ALCAR) treatment on the cognitive performance of patients clinically diagnosed with Alzheimer's disease. Early, small trials suggested a beneficial effect of ALCAR with respect to cognitive decline (98-100), whereas later, larger trials found little-to-no effect compared to placebo (101-103). However, a 2003 systematic review highlighted differences in methodologies between early and later studies that make it difficult to compare results (104). Nevertheless, the pooled analysis of 16 trials suggested improvements in the summary measure of patients' global functioning (assessed with the Clinical Global Impressions [CGI-I] scale) after 12 and 24 weeks of (but not after 52 weeks) of ALCAR treatment (1-3 g/day) and in cognitive performance (assessed with the Mini-Mental State Examination [MMSE] scale) after 24 weeks (but not at 12 or 52 weeks) (104). A 2003 meta-analysis of 21 trials found that ALCAR was superior to placebo in several psychometric tests assessing global patient functioning, attention, memory, and some intellectual functions (105).
Hepatic encephalopathy refers to the occurrence of a spectrum of neuropsychiatric signs or symptoms in individuals with acute or chronic liver disease (106). Subclinical hepatic encephalopathy may not feature any symptoms beyond abnormal behavior on psychometric tests or symptoms that are nonspecific in nature. In contract, overt hepatic encephalopathy can present with disorientation, obvious personality change, inappropriate behavior, somnolence, stupor, confusion, and coma (106). Changes in mental status are thought to be caused by the liver failing to detoxify neurotoxic compounds like ammonia. A 2019 systematic review of five placebo-controlled trials conducted by one group of investigators examined the effect of acetyl-L-carnitine (ALCAR) in 398 participants with cirrhosis and portal hypertension (high blood pressure in the portal vein) and presenting with either subclinical or overt hepatic encephalopathy. ALCAR was either administered orally (4 g/day for 90 days) in four trials or intravenously (4 g/day for three days) in one trial. ALCAR was found to significantly reduce blood ammonium concentration compared to placebo. However, none of the trials reported on serious adverse outcomes, including mortality. Additionally, the evidence was too limited to assess the impact on quality of life or mental and physical fatigue.
Fatigue is not uncommon in people who have undergone chemotherapy and survived cancer, with fatigue symptoms depending on the specific type of cancer and treatment. Cancer-related fatigue can persist well beyond the end of chemotherapy and be associated with cognitive and functional decline, insomnia, depression, and a reduction in the quality of life (107). A 2017 systematic review and meta-analysis identified 12 intervention studies that assessed the effect of L-carnitine or ALCAR on cancer-related fatigue (reported as a primary or secondary outcome) in cancer survivors (108). Three studies had no control arm, eight studies were open-label, and eight studies included fewer than 100 participants. Overall, only three studies were deemed of good quality. The meta-analysis of these three randomized, double-blind, placebo-controlled trials found no effect of L-carnitine (0.25-4 g/day for 1 week to 3 months) or ALCAR (3 g/day for 6 months) on the level of cancer-related fatigue (108).
L-Carnitine is concentrated in the epididymis, where sperm mature and acquire their motility (109). An early cross-sectional study of 101 fertile and infertile men found that L-carnitine concentrations in semen were positively correlated with the number of sperm, the percentage of motile sperm, and the percentage of normal appearing sperm in the sample (110), suggesting that L-carnitine may play an important role in male fertility. One placebo-controlled, double-blind, cross-over trial in 86 subjects with fertility issues found that supplementation with L-carnitine (2 g/day) for two months improved sperm quality, as evidenced by increases in sperm concentration and motility (111). In another placebo-controlled trial conducted by the same group, similar improvements in sperm motility were observed in participants supplemented with 2g/day of L-carnitine and 1 g/day of acetyl-L-carnitine (ALCAR) for six months (112). In both trials, the effect of carnitine was greater in the most severe cases of asthenozoospermia (reduced sperm motility) at baseline (111, 112). Another placebo-controlled, double-blind, randomized study in 44 men with idiopathic asthenozoospermia found an increase in sperm motility in those given ALCAR alone (3 g/day) or ALCAR (1 g/day) plus L-carnitine (2 g/day) compared to those given L-carnitine alone (2 g/day) or a placebo (113). However, a pooled analysis of the two trials that employed ALCAR found no significant effect of ALCAR and L-carnitine on sperm concentration, motility, and morphology (114). Evidence from larger scale clinical trials is still needed to determine whether L-carnitine and ALCAR could play a role in the treatment of male infertility.
Frailty is a syndrome prevalent among geriatric populations and characterized by a functional decline and a loss of independence to perform the activities of daily living. Frailty in individuals may include at least three of the following symptoms: unintentional weight loss, exhaustion (poor endurance), weakness (low grip strength), slowness, and physical inactivity (115). It is believed that early stages of frailty are amenable to interventions that could avert adverse outcomes, including the increased risk of hospitalization and premature death (116). The suggestion that carnitine deficiency may lead to frailty through mitochondrial dysfunction (117) has been examined in one trial. This randomized, double-blind, placebo-controlled trial in 58 older adults identified as "pre-frail" found an decrease in a Frailty Index score and an improvement in the hand grip test in individuals supplemented with L-carnitine (1.5 g/day) over 10 weeks but not in those given a placebo (118). However, there was no difference in Frailty Index and hand grip test scores between supplemental L-carnitine and placebo groups.
Loss of skeletal muscle mass is associated with a decrease in muscle strength and occurs with aging (119), as well as in several pathological conditions (120-122). Based on preclinical studies, it has been suggested that L-carnitine supplementation could limit the imbalance between protein anabolism (synthesis) and catabolism (degradation) that leads to skeletal muscle wasting (42). A randomized, double-blind, placebo-controlled trial in 28 older women (ages, 65-70 years) found no effect of L-carnitine supplementation (1.5 g/day for 24 weeks) on serum pro-inflammatory cytokine concentrations, body mass and composition (lean [fat-free] mass and skeletal muscle mass), or measures of skeletal muscle strength (123). In contrast, a retrospective cohort study in patients with cirrhosis found a reduced rate of skeletal muscle loss over at least six months in those who were administered L-carnitine (N=35; mean dose, 1.02 g/day) compared to those who were not (124). Of note, supplementation with L-carnitine was given in patients with cirrhosis to control hyperammonemia (N=27), to reduce muscle cramps (N=6), or to prevent carnitine deficiency (N=2). One major limitation of this study beyond its retrospective design is that patients who received L-carnitine had a significantly different clinical presentation; in particular, liver dysfunction was significantly more severe in these patients than in those who were not supplemented (124).
Muscle cramps are involuntary and painful contractions of skeletal muscles. Two uncontrolled studies conducted in participants with cirrhosis found that L-carnitine supplementation was safe to use at doses of 0.9 to 1.2 g/day for eight weeks (125) and 1 g/day for 24 weeks (126) and might be considered to control the frequency of cramps. However, whether supplemental L-carnitine can be efficacious to limit the incidence of muscle cramps in patients with cirrhosis remains unknown. An open-label, non-randomized trial in 69 patients with either type 1 or type 2 diabetes mellitus found a reduction in the incidence of muscle cramps and an improvement in the quality of life of those prescribed 0.6 g/day of L-carnitine for four months compared to controls (127). In contrast, there is little evidence to date to suggest that supplemental L-carnitine could reduce muscle cramps in patients undergoing hemodialysis (128). Well-designed trials are necessary to examine whether L-carnitine could be helpful in the management of cramps.
Interest in the potential of L-carnitine supplementation to improve athletic performance is related to its important roles in energy metabolism. A number of small, poorly controlled studies have reported that either acute (dose given one hour before exercise bout) or short-term (two to three weeks) supplementation with L-carnitine (2 to 4 g/day) supported energy production, cardiorespiratory fitness, and endurance capacity during physical exercise (reviewed in 129). However, in a double-blind, placebo-controlled trial in 32 healthy adults, propionyl-L-carnitine (1 g/day or 3 g/day) for eight weeks did not improve aerobic or anaerobic exercise performance (130). An intervention study compared the effect of L-carnitine supplementation (2 g/day for 12 weeks) on plasma and skeletal muscle carnitine concentrations and physical performance between 16 vegetarian and 8 omnivorous male participants (131). At baseline, plasma carnitine concentration was about 10% lower in vegetarian compared to omnivorous participants. However, the content carnitine in skeletal muscle, phosphocreatine, ATP, glycogen, and lactate, as well as measures of physical performance during exercise were equivalent between vegetarians and omnivores. While L-carnitine supplementation normalized plasma carnitine concentration in vegetarians to that observed in omnivores, there was no effect on energy metabolism and physical performance compared to no supplementation and between vegetarians and omnivores (131).
The normal rate of L-carnitine biosynthesis in humans ranges from 0.16 to 0.48 mg/kg of body weight/day (4). Thus, a 70 kg (154 1b) person would synthesize between 11 and 34 mg of carnitine per day. This rate of synthesis, combined with efficient (95%) L-carnitine reabsorption by the kidneys, is sufficient to prevent deficiency in generally healthy people, including strict vegetarians (132).
Meat, poultry, fish, and dairy products are the richest sources of L-carnitine, while fruit, vegetables, and grains contain relatively little L-carnitine. Omnivorous diets have been found to provide 23 to 135 mg/day of L-carnitine for an average 70 kg person, while strict vegetarian diets may provide as little as 1 mg/day for a 70 kg person (8). Between 54% and 86% of L-carnitine from food is absorbed, compared to 5%-25% from oral supplements (0.6-7 g/day) (13). Non-milk-based infant formulas (e.g., soy formulas) should be fortified so that they contain 11 mg/L of L-carnitine. Some carnitine-rich foods and their carnitine content in milligrams (mg) are listed in Table 1.
Intravenous L-carnitine is available by prescription only for the treatment of primary and secondary L-carnitine deficiencies (76).
Oral L-carnitine is available by prescription for the treatment of primary and secondary L-carnitine deficiencies (76). It is also available without a prescription as a nutritional supplement; supplemental doses usually range from 0.5 to 2 g/day.
Acetyl-L-carnitine (ALCAR) is available without a prescription as a nutritional supplement. In addition to providing L-carnitine, it provides acetyl groups that may be used in the formation of the neurotransmitter, acetylcholine. Supplemental doses usually range from 0.5 to 2 g/day (133).
Propionyl-L-carnitine is not approved by the US FDA for use as a drug to prevent or treat any condition. It is, however, available without prescription as a nutritional supplement.
See Figure 1 for the chemical structures of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine.
In general, L-carnitine appears to be well tolerated; no toxic effects have been reported in relation to intakes of high doses of L-carnitine. L-Carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. Supplements providing more than 3 g/day may cause a "fishy" body odor. Acetyl-L-carnitine (ALCAR) has been reported to increase agitation in some Alzheimer's disease patients (133). Despite claims that L-carnitine or ALCAR might increase seizures in some individuals with seizure disorders (133), these are not supported by any scientific evidence (134). Only the L-isomer of carnitine is biologically active; the D-isomer may actually compete with L-carnitine for absorption and transport, thereby increasing the risk of L-carnitine deficiency (4). Supplements containing a mixture of the D- and L-isomers (D,L-carnitine) have been associated with muscle weakness in patients with kidney disease. Long-term studies examining the safety of ALCAR supplementation in pregnant and breast-feeding women are lacking (133).
Pivalic acid combines with L-carnitine and is excreted in the urine as pivaloylcarnitine, thereby increasing L-carnitine losses (see also Secondary carnitine deficiency). Consequently, prolonged use of pivalic acid-containing antibiotics, including pivampicillin, pivmecillinam, pivcephalexin, and cefditoren pivoxil (Spectracef), can lead to secondary L-carnitine deficiency (135). The anticonvulsant valproic acid (Depakene) interferes with L-carnitine biosynthesis in the liver and forms with L-carnitine a valproylcarnitine ester that is excreted in the urine. However, L-carnitine supplements are necessary only in a subset of patients taking valproic acid. Risk factors for L-carnitine deficiency with valproic acid include young age (<2 years), severe neurological problems, use of multiple antiepileptic drugs, poor nutrition, and consumption of a ketogenic diet (135). There is insufficient evidence to suggest that nucleoside analogs used in the treatment of HIV infection (i.e., zidovudine [AZT], didanosine [ddI], zalcitabine [ddC], and stavudine [d4T] or certain cancer chemotherapy agents (i.e., ifosfamide, cisplatin) increase the risk of secondary L-carnitine deficiency (135).
Originally written in 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in April 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in April 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in July 2019 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in December 2019 by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, Dept. of Biochemistry and Biophysics
Helen P. Rumbel Professor for Healthy Aging Research
Oregon State University
Copyright 2002-2020 Linus Pauling Institute
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