L-carnitine, an amino acid derivative, is found in nearly all cells of the body. L-carnitine transports long-chain fatty acids across the inner mitochondrial membranes in the mitochondria, where they are processed by beta-oxidation to produce biological energy in the form of adenosine triphosphate or ATP.
L-carnitine is known chemically as (R)-3-carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, inner salt; beta-hydroxy-gamma-N,N,N-trimethylaminobutyrate; gamma-amino-beta-hydroxybutyric acid trimethylbetaine; (3-carboxy-2-hydroxypropyl) trimethylammonium hydroxide, inner salt; gamma-trimethyl-beta-hydroxybutyrobetaine, and 3-hydroxy-4-(trimethylammonio) butanoate. L-carnitine is also known as levocarnitine and was formerly called vitamin BT. L-carnitine is a quarternary amine and belongs to the same chemical family as choline and is soluble in water. L-carnitine is represented by the following chemical structure:
L-carnitine occurs naturally in animal products. Generally, only very small amounts of it are found in plants, with few exceptions, such as avocado and some fermented soy products, e.g. tempeh. L-carnitine is a chiral molecule. Its stereoisomer D-carnitine does not have the biological activity of L-carnitine and may even antagonize L-carnitine in its biological roles.
L-carnitine is synthesized in the human body, chiefly in the liver and kidneys, from the essential amino acids L-lysine and L-methionine. Niacin, vitamins B6 and C, and iron are involved in its biosynthesis. L-carnitine is described as a conditionally essential nutrient. This refers to certain conditions where exogenous L-carnitine may be required, such as in long-term parenteral nutrition, those on valproic acid therapy and possibly for the elderly.
L-carnitine is available in a few forms. Oral L-carnitine is available as a nutritional supplement and as a prescribed orphan drug treatment for primary and secondary L-carnitine deficiencies. Intravenous L-carnitine (levocarnitine) is available as a prescription orphan drug for the treatment of primary and secondary L-carnitine deficiencies. Acetyl-L-carnitine, another delivery form of both L-carnitine and acetyl groups, is available as a nutritional supplement. Another delivery form of L-carnitine, proprionyl-L-carnitine, is available in Europe but not at present in the U.S.
Actions & Pharmacology
Supplemental L-carnitine may have cardioprotective activity in addition to beneficially affecting cardiac function. It may have a triglyceride-lowering effect in some as well as help to elevate HDL-cholesterol levels. L-carnitine may also have antioxidant properties.
Acetyl-L-carnitine may have neuroprotective activity. It may also aid in the treatment of age-related cholinergic deficits, such as those found in dementia disorder, including Alzheimer's disease (see Acetyl-L-carnitine).
Mechanism of Action
There are at least two major functions of L-carnitine. All tissues except the brain use long-chain fatty acids for bioenergy production. In cardiac and skeletal muscle, a major contribution of bioenergy comes from the beta-oxidation of long-chain fatty acids. Long-chain fatty acids require L-carnitine to transport them across the inner membranes of the mitochondria, wherein their metabolism produces bioenergy. Following the delivery of long-chain fatty acids into other mitochondria, L-carnitine, either by itself or esterified to an acyl group, recrosses the mitochondrial membrane to allow for continual use in this shuttle process.
Another function of L-carnitine is to remove short-chain and medium-chain fatty acids from the mitochondria in order to maintain coenzyme A levels in these organelles. These fatty acids accumulate as a result of normal and abnormal metabolism. This mechanism prevents the build-up in the mitochondria of short-chain and medium-chain fatty acids that may interfere with the bioenergy-producing process vital to the normal function of the cell.
Two types of L-carnitine deficiency states exist: primary systemic carnitine deficiency (SCD) and secondary carnitine deficiency syndromes. SCD is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycemia and hyperammonemia. SCD appears to be due, in part, to loss of function of the transporter protein called OCT N2, which helps carry L-carnitine into cells. Patients with SCD have low L-carnitine levels in liver and skeletal muscle and variable concentrations of L-carnitine in the serum. Treatment with large doses of L-carnitine either orally or intravenously is sometimes beneficial in this rare genetic disorder.
Secondary L-carnitine deficiency disorders include a large number of entities. Some of these are genetic defects of metabolism such as methylmalonic aciduria, cytochrome C oxidase deficiency, fatty acyl-coenzyme A dehydrogenase deficiency, including long-chain and medium-chain deficiency, isovaleric acidemia, glutaric aciduria and propionic acidemia.
The mechanism of L-carnitine deficiency in these disorders is unclear. Some hypothesize that an accumulation of short-chain and medium-chain fatty acyl CoA molecules occurs in the mitochondria because insufficient L-carnitine is available to expel them. This accumulation would disturb the bioenergy-producing processes of the mitochondria. Symptoms of secondary muscle L-carnitine deficiency, not surprisingly, include muscle weakness and fatigue.
Secondary L-carnitine deficiency may also be found secondary to other conditions such as chronic renal failure treated by hemodialysis, cirrhosis with cachexia, chronic severe myopathies, myxedema, hypopituitarism, adrenal insufficiency, hyperammonemia associated with valproic acid therapy, valproate-induced Reye's syndrome, advanced AIDS and pregnancy. It may also be seen in those with HIV who are being treated with the nucleoside analogues didanosine (ddI), zalcitabine (ddC) and stavudine (d4T). In addition, it may occur in premature infants receiving parenteral nutrition. There is some preliminary evidence that secondary L-carnitine deficiency may also be associated with aging.
L-carnitine may possess antioxidant properties. A disturbance in long-chain fatty acid oxidation in mitochondria and/or the accumulation of small-chain and medium-chain fatty acyl CoA molecules in the mitochondria might be expected to increase oxidative stress. There is some evidence that proprionyl-L-carnitine, a delivery form of L-carnitine, might protect the ischemic heart from reperfusion injury via an antioxidant effect.
About 60 to 75% of L-carnitine from food is absorbed. The percentage absorbed from supplements appears to be lower. In one study only 20% of a 2-gram dose of L-carnitine was found to be absorbed following ingestion. Most of an ingested dose of L-carnitine is absorbed by the small intestine, apparently by facilitative diffusion and active transport. Following the administration of a dose of L-carnitine of 1,980 milligrams twice daily, the maximum plasma concentration level (Cmax) was 80 nanomoles per milliliter, and the time to maximum concentration (Tmax) occurred at 3.3 hours. The bioavailability of oral L-carnitine is about 15%. L-carnitine is not bound to plasma protein or albumin.
Five normal adult male volunteers, administered a dose of [3 H-methyl]-L-carnitine following 15 days of a high-carnitine diet and additional L-carnitine supplement, excreted 58 to 65% of administered radioactive dose in 5 to 11 days in the urine and feces. Maximum concentration of [3 H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hours after radioactive L-carnitine administration. Major metabolites found were trimethyl N-oxide, primarily in urine (8% to 49% of the administered dose) and [3 H]-gamma-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Fecal excretion of total L-carnitine was less then 1% of total L-carnitine excretion. After attainment of steady state following four days of oral administration of about 2,000 milligrams twice a day of L-carnitine, urinary excretion of L-carnitine was about 9% of the orally administered dose. Approximately 95% of filtered L-carnitine is reabsorbed in healthy humans. Hypothyroidism decreases the urinary excretion of L-carnitine, while hyperthyroidism increases it.
Following absorption from the intestine, about 25% of L-carnitine may be acylated in the intestinal mucosa. Orally administered L-carnitine and its acylated metabolite are distributed to most tissues of the body. Uptake of L-carnitine into cells is thought to occur by facilitative diffusion and, in some cases, by active transport. Most of the body's stores of L-carnitine are found in cardiac and skeletal muscle.
Indications & Usage
The strongest evidence for the use of supplemental L-carnitine may be in the management of cardiac ischemia and peripheral arterial disease. It may also more generally be indicated for cardioprotection. It lowers triglyceride levels and increases levels of HDL-cholesterol in some. It is used with some benefit in those with primary and secondary carnitine deficiency syndromes. There is less evidence to support arguments that carnitine is indicated in liver, kidney and immune disorders or in diabetes and Alzheimer's disease. There is little evidence that supplemental L-carnitine boosts energy, increases athletic performance or inhibits obesity. There is no support for the claim that healthy vegetarians require L-carnitine supplementation.
There have been no reports of toxicity from L-carnitine overdosage. The oral LD50 of L-carnitine in mice is 19.2 grams per kilogram.
L-carnitine is available in a few forms. Oral L-carnitine is available as a nutritional supplement and as a prescribed treatment for primary and secondary L-carnitine deficiencies. Intravenous L-carnitine is available as a prescription drug for the treatment of primary and secondary L-carnitine deficiencies. Acetyl-L-carnitine is available as a nutritional supplement. Propionyl-L-carnitine is available in Europe but not currently in the United States. DL-carnitine should be avoided. The available salts of L-carnitine are L-carnitine HC1, L-carnitine tartrate and L-carnitine fumarate.
Those who take supplemental L-carnitine for cardiovascular health (and most other possible indications) take 500 milligrams to 2 grams daily. The higher amounts are taken in divided doses. The doses are taken with or without food.
See Physician's Desk Reference for dosage and administration of levocarnitine in the treatment of primary and secondary L-carnitine deficiencies. See Acetyl-L-carnitine for dosage of this supplement.
LiteratureBohles H, Richter K, Wagner-Thiesson E, Schafer H. Decreased serum carnitine in valproate induced Reye syndrome. Eur J Pediatr. 1982; 139:185-186.Bohmer T, Rynding A, Solberg HE. Carnitine levels in human serum in health and disease. Clin Chim Acta. 1974; 57:55-61.Borum PR. Carnitine. Ann Rev Nutr. 1983; 3:233-259.Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol. 1999; 35:1618-1624.Brevetti G, Chiarello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease: a double-blind, cross-over study. Circul. 1988; 77:767-773.Brooks H, Goldberg L, Holland R, et al. Carnitine-induced effects on cardiac and peripheral hemodynamics. J Clin Pharmacol. 1977; 17:561-578.Christiansen R, Bremer J. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochem Biophys Acta. 1977; 448:562-577.de Simone C, Famularo G, Tzantzoglov S, et al. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of L-carnitine. AIDS. 1994; 8:655-660.Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS. 1997; 11:185-190.Lindstedt S, Lindstedt G. Distribution and excretion of carnitine 14CO2 in the rat. Acta Chim Scand. 1961; 15:701-702.Maebashi M, Kawamura N, Sato M, et al. Lipid-lowering effects of carnitine in patients with type-IV hypolipoproteinaemia. Lancet. 1978; 2:805-807.Marzo A, Arrigoni Martelli E, Mancinelli A, et al. Protein binding of L-carnitine family components. Eur J Drug Met Pharmacokin Special Issue III. 1992; 364-368.Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Gen. 1999; 21:91-94.Opie LH. Role of carnitine in fatty acid metabolism of normal and ischemic myocardium. Am Heart J. 1979; 97:375-388.Levocarnitine. Physicians' Desk Reference. 54 ed. Montvale, NJ; Medical Economics Company. 2000:2957-2959.Pola P, Savi L Grilli M, et al. Carnitine in the therapy of dyslipidemic patients. Curr Therapeu Res. 1980; 27:208-216.Prockup LD, Engel WK, Shug AL. Nearly fatal muscle carnitine deficiency with full recovery after replacement therapy. Neurol. 1983; 33:1629-1631.Rebouche CJ. Carnitine. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore, MD: Williams & Wilkins; 1999:505-512.Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992; 6:3379-3386.Rebouche CJ, Engel AG. Carnitine metabolism and deficiency syndromes. Mayo Clin Proc. 1983; 58:533-540.Rebouche CJ, Paulson DJ. Carnitine metabolism and function in humans. Ann Rev Nutr. 1986; 6:41-68.Rossi CS, Siliprandi N. Effects of carnitine on serum HDL-cholesterol: report of two cases. Johns Hopkins Medical J. 1982; 150:51-54.Sachan DS, Rhew TH, Ruark RA. Ameliorating effects of carnitine on alcohol-induced fatty liver. Am J Clin Nutr. 1984; 39:738-744.Triggs WJ, Bohan TP, Shen-Nan L, Wilmore J. Valproate-induced coma with ketosis and carnitine insufficiency. Arch Neurol. 1990; 47:1131-1133.Vacha GM, Giorcelli G, Siliprandi N, Corsi G. Favorable effects of L-carnitine treatment on hypertriglyceridemia in hemodialysis patients: decisive role of low levels of high-density lipoprotein-cholesterol. Am J Clin Nutr. 1983; 38:532-540.
Research & Summary
Favorable results have been reported for many years with regard to the use of L-carnitine in the treatment of various forms of cardiovascular disease. The walking capacity of patients with intermittent claudication was significantly improved in one double-blind, cross-over study of patients receiving oral L-carnitine. The data in this study suggests that L-carnitine enhances pyruvate utilization and oxidative phosphorylation efficiency in the skeletal muscle of the ischemic leg.
In a more recent, multicenter study, propionyl-L-carnitine was compared with placebo in the treatment of those with peripheral arterial disease of the legs. The study of 162 patients receiving propionyl-L-carnitine and 166 patients receiving placebo continued for one year. Walking ability and quality of life were evaluated at regular intervals. Those initially presenting with the most severe disability (able to walk no more than 250 meters) exhibited significant improvement, increasing walking distance by 98 meters compared with 54 meters in the placebo group. Those able to walk more than 250 meters at baseline also improved, versus placebo, but not at a level of statistical significance.
Supplemental L-carnitine has been helpful in some rare primary genetic L-carnitine deficiency syndromes, as well as in more common secondary L-carnitine deficiency syndromes (see pharmacology). It has been estimated that about 40% of those with the myopathies associated with the secondary deficiency syndromes respond to dietary L-carnitine, evidenced by enhanced muscle strength and reduced myoglobinuria.
An indirect role for supplemental L-carnitine in some forms of liver disease is suggested, because hepatic disease impairs the last stage of L-carnitine synthesis resulting in L-carnitine deficiencies in heart and skeletal muscle. Preliminary work suggests that L-carnitine can reduce fat deposits in some fatty livers. Research is ongoing.
The kidney is also an important locus of carnitine synthesis. Chronic kidney disease may eventually be an indication for L-carnitine supplementation, but more research is needed to demonstrate this. There is some evidence that dialysis patients can benefit from L-carnitine supplementation since dialysis removes the low-molecular-weight L-carnitine.
There is no evidence that L-carnitine will prevent diabetes, although abnormal carnitine metabolism is associated with diabetes. Ongoing research may demonstrate some benefit from L-carnitine supplementation. Animal model work in diabetes has shown improved myocardial function with administration of parenteral L-carnitine.
The claim that L-carnitine may have beneficial effects in Alzheimer's disease is unproved. Acetyl-L-carnitine, a derivative of L-carnitine and a delivery form of the substance, on the other hand, has shown some very preliminary benefit in this regard (see Acetyl-L-Carnitine). Investigation of L-carnitine may have some positive impact on some immune disorders, including AIDS. In a study of 20 patients with advanced AIDS, subjects were randomly assigned to receive either placebo or 6 grams of L-carnitine daily. At baseline, L-carnitine concentrations in the peripheral blood mononuclear cells (PBMC) of the AIDS patients were found to be lower than in healthy controls, even though the AIDS patients had normal serum concentrations of L-carnitine.
The study continued for two weeks. It demonstrated a significant trend toward restoration of normal intracellular L-carnitine levels. This increase in cellular L-carnitine was strongly associated with improved lymphocyte proliferative responsiveness to mitogens. The researchers suggested that ""L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.'' The study also noted a significant decrease in the triglyceride levels of those patients receiving L-carnitine supplements. More research is clearly warranted.
L-carnitine effects on immunity are suggested, as well, from animal model work. Reductions in circulating cytokines and tumor necrosis factor have been observed.
There is little convincing evidence that L-carnitine supplements have any significant impact on physical performance or obesity. There is no support for the claim that vegetarians, including strict vegetarians, require L-carnitine supplementation. There is no evidence of carnitine deficiency in this population. Plasma carnitine concentrations in strict vegetarians are only an insignificant 10% lower than in omnivores.
Contraindications, Precautions & Adverse Reactions
Known hypersensitivity to an L-carnitine-containing product.
Standard assays for mutagenicity indicate that L-carnitine is not mutagenic.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human doses used for the treatment of primary and secondary L-carnitine deficiency on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to L-carnitine. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, supplemental L-carnitine should be used by pregnant women only if clearly indicated and only under medical supervision. It is not known whether L-carnitine is excreted in human milk. Supplemental L-carnitine is not advised for nursing mothers. Those with seizure disorders should only use L-carnitine under medical advisement and supervision.
Mild gastrointestinal symptoms have been reported in those taking oral L-carnitine, including transient nausea and vomiting, abdominal cramps and diarrhea. Mild myasthenia has been reported in uremic patients taking the racemic mixture D,L-carnitine. There are no reports of mild myasthenia in uremic patients receiving L-carnitine. Supplemental L-carnitine is generally well tolerated.
Although the incidence is low, seizures have been reported to occur in those with or without pre-existing seizure disorders receiving either oral or intravenous L-carnitine. In those with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.
Therapy with valproic acid, the nucleoside analogues didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) may produce secondary L-carnitine deficiencies. So might the pivalic acid-containing antibiotics, pivampicillin, pivmecillinam and pivcephalexin. These antibiotics are used in Europe.
Choline supplementation may lead to increased L-carnitine retention. Vitamin C deficiency may lead to secondary L-carnitine deficiency.