The two-day conference held March 25-26, 2004 at the Lister Hill Auditorium in Bethesda, Maryland, 2004 was sponsored by the National Institute of Child Health and Human Development, the National Center for Complementary and Alternative Medicine, the National Institute of Mental Health, and the Office of Dietary Supplements. The overall conference goals were to: 1) provide the scientific and lay communities with the most updated, evidence-based information regarding the role of carnitine in health and disease prevention; 2) clarify issues relevant to appropriate uses of carnitine; and 3) propose new areas of research for future studies on this nutrient.
The first day addressed the fundamentals of carnitine physiology and pharmacology, issues related to its replacement in health and disease, its effects on skeletal and cardiac or smooth muscle, and its role in fat metabolism and obesity. Day two addressed the role of carnitine and acyl-carnitines in aging, its role in immunity and HIV infection, and new perspectives in carnitine research. The conference closed with a summarization of highlights and research needs. Outlined below is a summary and research needs emerging from this conference. This is followed by a synopsis of each speaker's presentation and their presentation. To view a presentation, click on the link to that presentation.
The name carnitine is derived from the Latin "carnus" or flesh, as the compound was first isolated from meat. Carnitine is termed a conditionally essential nutrient, as under certain conditions its requirements may exceed the individual's capacity to synthesize it. Carnitine mediates the transport of medium/long-chain fatty acids across mitochondrial membranes, facilitating their oxidation with subsequent energy production; in addition, it facilitates the transport of intermediate toxic compounds out of the mitochondria preventing their accumulation. Because of these key functions, carnitine is concentrated in tissues that utilize fatty acids as their primary dietary fuel, such as skeletal and cardiac (heart) muscle. Dietary sources of carnitine include foods of animal origin, such as meat and dairy products. In general, healthy adults do not require dietary carnitine as carnitine stores are replenished through endogenous synthesis from lysine and methionine in the liver and kidneys. Excess carnitine is excreted via the kidneys. In the US, carnitine is an approved prescription drug for the treatment of primary systemic carnitine deficiency and secondary carnitine deficiency syndromes. Carnitine is also available over-the-counter as a dietary supplement, as an aid to weight loss, to improve exercise performance, and to enhance a sense of well-being.
Carnitine is the generic term for a number of compounds that include L-carnitine, L-acetylcarnitine, acetyl-L-carnitine, and L-propionyl carnitine. The only forms available over-the-counter in the US are L-carnitine and acetyl-L-carnitine. L-carnitine is the biological active form. The D-isomer, which is not biologically active, can compete with the L-isomer potentially increasing the risk of L-carnitine deficiency. Proprionyl-L-carnitine is approved for use in Europe but not in the US.
Carnitine is studied extensively in part because of the important role it plays in fatty acid oxidation and energy production, and because it is a well-tolerated and generally safe therapeutic agent. It is proven treatment in children who have recessive defects in the carnitine transporter system and in individuals treated with pivalate containing antibiotics. Other benefits attributed to carnitine result from the management of secondary carnitine deficiencies. These benefits are supported by preliminary findings and need to be confirmed through well-controlled randomized trials. While there is agreement on carnitine's role as a prescription product for the treatment of primary carnitine deficiencies, its benefits as a dietary supplement in individuals who are carnitine sufficient is debated.
Carnitine research needs emerging from this conference can be grouped under three broad headings, i.e. basic research, as a drug in the treatment and management of disease conditions, and as a dietary supplement. These needs are outlined below.Basic research needs:
As a drug in the treatment and management of disease conditions:
- Determine the structures of other carnitine acyltranferases. The crystalline structure of mouse carnitine acetyltransferace or CRAT was presented at the conference.
- Understanding the molecular basis for the disease caused by mutations of the carnitine palmitoyltransferase (CPT)I and CPTII enzymes involved in the transport of fatty acids by L-carnitine into and out of the mitochondria.
- Understand how malonyl CoA inhibits CPT. Malonyl CoA is a potent inhibitor of this enzyme.
- Determine whether the benefits of oral carnitine supplements accrue from an increase in intracellular carnitine concentrations or from an increased intracellular to extracellular exchange of carnitine and acylcarnitine.
- Understand how orally, administered acylcarnitine is absorbed, i.e. is it absorbed intact, if not, where the acyl and carnitine moieties go.
- Understand the potential positive and negative effects of carnitine and/or acylcarnitine ester supplementation on pathways other than fatty acid oxidation, such as in the regulation of gene transcription.
- Evaluate the biochemical, pharmacological and physiological determinants of the response to carnitine supplementation.
As dietary supplements:
- In the treatment of non-alcoholic steatohepatitis (NASH). Steatohepatitis or fat deposits in the liver can result from obesity, diabetes, long-term use of steroids and the antibiotic tetracycline.
- Identifying the specific acylcarnitine that accumulates in peripheral arterial disease in order to determine the specific metabolic disruption. Patients with peripheral arterial disease, who become symptomatic with claudication, have a marked impairment in exercise performance and overall functional capacity.
- Determine the benefits of carnitine supplementation in the prevention of osteoporosis in post-menopausal women who depend on life-long thyroid stimulating hormone (TSH) -suppressive L-T4 therapy for the management of thyroid cancer.
- Determine the benefits of carnitine supplementation as prophylaxis or ancillary therapy of serious hyperthyroidism in elderly patients on the antiarrhythmic drug amiodarone.
- Determine whether carnitine supplementation can improve symptoms other than fatigue in cancer patients. In addition, test the interaction between carnitine and antineoplastics agents used in cancer treatment.
- Determine the benefits of carnitine supplements in individuals who do not have a defect in fatty acid oxidation. As these benefits are likely to be subtle, develop improved methods to measure the beneficial effects accrued from carnitine supplementation.
- Develop well-designed, adequately powered clinical trials of carnitine supplementation that include robust clinical performance endpoints and information relevant to understanding potential mechanisms of action.
- Determine whether carnitine supplements improve sperm quality and quantity.
- Determine whether high-protein, high-fat diets (Atkins-type diets) increase carnitine requirements.
- Research to prove benefits in certain states that alter the requirements for carnitine, such as in pregnancy, and in those under physical or psychological stress.
Owen M. Rennert, Scientific Director, NICHD, NIHMarc R. Blackman, (PDF, 132 KB)Chief, Endocrine Section, Laboratory of Clinical Investigation, NCCAM, NIH Plenary Session I: The Carnitine System in Human Metabolism
Chair: Marc R. Blackman, Chief, Endocrine Section, Laboratory of Clinical Investigation, NCCAM, NIH, Bethesda, MarylandThe Role of the Carnitine System in Human MetabolismDaniel W. Foster (PDF, 913 KB)Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
A biological definition of human life is the ability to generate high-energy phosphate bonds, principally adenosine triphosphate (ATP) from oxidizable external and internal fuels. The proportion of the hormones glucagon to insulin is critical to this process. During the anabolic phase, or fed state, external fuels are metabolized under the influence of insulin for energy with excess stored as fat and glycogen. During the catabolic phase, or fasted state, internal fuels such as fatty acids become the primary source of fuel for the body. Glycogen is utilized under the influence of glucagon to meet energy needs of the brain. During the catabolic phase, the liver becomes an organ of energy production rather than glucose storage.
Long-chain fatty acids are metabolized to generate energy in the mitochondria. Four enzymes are required for transporting these fatty acids by L-carnitine into the mitochondrial matrix. These enzymes located on the outer and inner mitochondrial membranes, are: 1) carnitine palmitoyltransferase 1 A (CPTI liver form); 2) carnitine palmitoyltransferase 1B (muscle form), 3) acylcarnitine translocase, and 4) carnitine palmitoyltransferase II (CPTII). On the outer mitochondrial membrane, CPTI catalyzes the formation of acylcarnitine from acyl-coenzyme A (CoA). Acylcarnitine translocase transports acylcarnitine across the inner mitochondrial membrane, and CPTII associated with the inner mitochondrial membrane catalyzes the formation of acyl-CoA through a process called beta-oxidation, yielding propionyl-CoA and acetyl-CoA. The on/off signal for fatty acid oxidation is mediated by concentrations of malonyl coenzyme A, which is the primary negative regulator of CPT1.
An imbalance of the CPT system can cause acutely fatal illness. Diabetic ketoacidosis is a classic example of gain, and systemic carnitine deficiency is a classic example of loss. These concepts are illustrated in Dr Foster's presentation. Session 1: Carnitine Physiology and Pharmacology: The Basics
Chair: Marc R. Blackman, Chief, Endocrine Section, Laboratory of Clinical Investigation, NCCAM, NIH, Bethesda, MarylandStructure and Function of Carnitine AcyltranferasesLiang Tong (PDF, 1 MB)Movie 1 (Quicktime, 4 MB)Movie 2 (Quicktime, 5 MB)Department of Biological Sciences, Columbia University, New York, New York
Carnitine acyltranferases catalyze the exchange of acyl groups between carnitine and coenzyme A (CoA). The enzymes include carnitine acetyltransferase (CRAT), which transport short-chain fatty acids, carnitine octanoyltransferase (COT), which transport medium-chain fatty acids, and carnitine palmitoyltransferase (CPT) which transport long-chain fatty acids. In his laboratory, Dr. Tong and his colleagues have determined the crystal structures of mouse CRAT, alone and in complex with its substrates, carnitine or CoA. CRAT contains two domains, which share the same backbone fold. The active site is located at the interface between the two domains in a tunnel that extends through the center of the enzyme. Carnitine and CoA are bound in this tunnel. This structural knowledge provides a molecular basis for understanding the catalysis by CRAT. As mutation or dysregulation of the CPT enzymes are linked to serious disease states, these enzymes are promising targets for the development of therapeutic agents against Type 2 diabetes and obesity. The crystal structures of CRAT can be viewed in Dr. Tong's presentation.Overview of Physiological and Pharmacological Actions Charles J. Rebouche (PDF, 984 KB)Associate Professor, Department of Pediatrics, University of Iowa, Iowa City, Iowa
In the human body, the L-carnitine pool consists of nonesterified L-carnitine and several acyl-carnitine esters. Acetyl L-carnitine (ALC) is the most important of these esters. Carnitine homeostasis is maintained by dietary intake, some synthesis, and efficient renal reabsorption. Dietary carnitine is absorbed by active and passive transfer in the intestine. Absorption is dependent on both the dose and dietary source. Between 54 - 87% of carnitine is absorbed from food and 14-18% from supplements. Absorption from supplements is primarily passive. The kidneys are an important regulator of carnitine homeostasis. At normal circulating levels reabsorption of carnitine in the kidneys is highly efficient (90-99% of filtered load). When circulating levels increase, renal reabsorption decreases, resulting in their normalization. Circulating carnitine is distributed between two compartments, large and slow turnover (i.e. the muscle), and small and rapid turnover (i.e., the liver, kidney, and other tissues). At normal dietary intakes whole-body turnover in humans is 38-119 hours. Ingestion of 2 g of ALC increased circulating levels by 43%, suggesting that ALC is absorbed partially unhydrolyzed. After intravenous administration of 0.5 g of ALC, ALC is rapidly hydrolyzed, and ALC and L-carnitine concentrations return to baseline within 12 hours. Further research is needed to determine whether repeated dosing of L-carnitine results in increased circulating and tissue concentrations. Session 2: Carnitine Replacement
Chair: Paul Coates, Director, Office of Dietary Supplements (ODS), NIH, Bethesda, MarylandCarnitine Deficiency Disorders in Children Charles Stanley (PDF, 181 KB)Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Carnitine plays a key role in fatty acid oxidation. Because of this role, there is interest as to whether carnitine supplementation is beneficial in genetic or acquired disorders of energy production to improve fatty acid oxidation, to remove accumulated toxic fatty acyl-CoA metabolites, or to restore the balance between free and acyl-CoA. There are two known disorders in children where the carnitine supply becomes limiting for fatty acid oxidation, and supplementation with carnitine is essential: 1) a recessive genetic defect of the muscle/kidney sodium-dependent, plasma membrane carnitine transporter, which presents as cardiomyopathy or hypoketotic hypoglycemia in infancy, and 2) chronic administration of pivalate conjugated antibiotics, in which excretion of pivaloyl-carnitine can result in carnitine depletion. In the latter situation, tissue levels may become low enough to limit fatty acid oxidation. The benefits of carnitine supplementation in secondary carnitine deficiencies may require invasive endurance studies of fasting ketogenesis or muscle and cardiovascular work, as carnitine becomes rate limiting only at very low concentrations.Carnitine Replacement in End-Stage Renal Disease and HemodialysisMenotti Calvani (PDF, 1.5 MB)Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Rome, Italy
The kidneys are an important regulator of carnitine homeostasis. During chronic renal failure, serum carnitine levels increase because of decreased renal clearance. A high acylcarnitine/free carnitine ratio is found is these patients, because renal synthesis and excretion are both decreased. On the other hand, patients undergoing dialysis present with low plasma carnitine levels resulting from a number of factors, including efficient removal during dialysis, impaired biosynthesis, and reduced protein intakes. Carnitine levels can fall to 40% of baseline levels during dialysis, but increase during the interdialysis period. Repeated dialysis can result in depletion of carnitine in skeletal muscle. Supplementation with carnitine improves circulating and tissue levels resulting in benefits to the overall well-being of these patients. Session 3: Carnitine Effects on Muscle: Skeletal, Cardiac, or Smooth
Chair: Rebecca Costello, Deputy Director, Office of Dietary Supplements (ODS), NIH, Bethesda, MarylandCarnitine and Sports Medicine: Use or Abuse?Eric P. Brass (PDF, 113 KB)Center for Clinical Pharmacology, Department of Medicine, Harbor-UCL, Torrance, California
Carnitine has important roles in skeletal muscle bioenergetics. Decreased concentrations of carnitine in skeletal muscle results in impairment of muscle function. This effect has led to the belief that carnitine supplementation can improve skeletal muscle function and athletic performance in healthy individuals. Despite this hypothesis, 20 years of research has provided no compelling evidence that carnitine supplementation can improve athletic performance. Several factors account for the lack of a positive effect: 1) muscle carnitine content is tightly regulated and levels are not easily increased with supplementation, 2) data on the optimal relationship between muscle carnitine content and muscle metabolic function are not available. Extrapolation of existing data suggests that only very low levels of carnitine are needed to support muscle function, 3) it is unclear as to whether carnitine supplementation can alter regulation of fuel homeostasis, and 4) tests sensitive enough to measure small changes in athletic performance as a result of carnitine supplementation are not available. Although data are not available to support a positive effect of carnitine on athletic performance, a negative finding has not been proven either. Thus, the absence of evidence of a benefit is not evidence of absence of a benefit.Therapeutic Effects of L-Carnitine and Propionyl-L-Carnitine on Cardiovascular Diseases: A ReviewRoberto Ferrari (PDF, 3.4 MB)Cattedra di Cardiologia, Universitá degli Studi di Brescia, Brescia, Italy
Carnitine is concentrated in cardiac muscle, which uses fatty acids as its primary fuel. Studies show that carnitine can reduce myocardial injury after ischemia and reperfusion by counteracting the toxic effects of free fatty acids and improving carbohydrate metabolism. In short-term studies, carnitine has been shown to have anti-ischemic properties. The results from two large multicenter trials conducted in Italy (CEDIM 1 and 2) showed that administration of intravenous and oral carnitine at relatively high amounts reduced mortality and heart failure. This presentation describes the findings from these studies.Carnitine and Peripheral Arterial DiseaseWilliam R. Hiatt (PDF, 493 KB)University of Colorado Health Sciences Center, Denver, Colorado
Patients with peripheral arterial disease, who become symptomatic with claudication, have a marked impairment in exercise performance and overall functional capacity. Claudication results from temporary inadequate supply of oxygen to the muscles of the leg, and by accumulation of muscle acylcarnitine. Supplementation with L-carnitine and propionyl-L-carnitine may improve metabolism and exercise performance of ischemic muscles. Preliminary studies show that L-carnitine improves treadmill performance, while propionyl-L-carnitine improves walking distance. Propionyl-L-carnitine is not currently approved for use in the U.S.Session 3: Carnitine, Fat Metabolism, and Obesity
Chair: Michael J. Quon, Chief, Diabetes Unit, Laboratory of Clinical Investigation, NCCAM, NIH, Bethesda, MarylandCarnitine in Type 2 DiabetesGeltrude Mingrone (PDF, 1.27 MB)Istituto di Medicina Interna, Catholic University, Roma, Italy
Insulin resistance plays an important role in the pathogenesis of type 2 diabetes. One question is whether mitochondrial dysfunction might be a factor in the development of type 2 diabetes, and whether insulin resistance is associated with a defect in muscle fatty acid oxidation. Intramyocellular lipid levels have become a marker for insulin resistance, and an inverse relationship between insulin sensitivity and intramyocellular lipid content has been demonstrated in humans. Research shows that insulin resistance in skeletal muscle cells from children of patients with type 2 diabetes is associated with altered fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation. Preliminary data suggest that supplementation with L-carnitine can improve insulin sensitivity in individuals with type 2 diabetes, as evidenced in part by its ability to decrease intramyocellular lipid levels.Plenary Session II: Carnitine and Acyl-Carnitines in Aging
Chair: Husseini Manji, Director, Molecular Pathology, National Institute of Mental Health (NIMH), NIH, Bethesda, MarylandDelaying the Mitochondrial Decay of Aging with Acetyl CarnitineBruce N. Ames (PDF, 1.12 MB)University of California, Berkeley, California
A decline in mitochondrial function is thought to be major contributor to the aging process. Tissue L-carnitine levels also decline with age. Further, mitochondrial decay increases oxidative damage to proteins with age, leading to structural deformation of key enzymes and decreased affinity for the enzyme's substrate. In old rats, this decay can be reversed by supplementation with acetyl-carnitine and alpha-lipoic acid. Moreover, supplementation with a combination of the two was found to be more effective than the use of either compound alone. L-carnitine may also be effective in the treatment of mild cognitive impairment and mild Alzheimer's disease, as suggested by a recent meta-analysis of 21 double-blind clinical trials. Other studies suggest that alpha-lipoic acid may be effective in the treatment of neuropathic deficits in diabetes.Session 5: Carnitine, Immunity, and HIV Infection
Chair: Carlos Zarate, NIMH, NIH, Bethesda, MarylandImmunomodulatory Properties of CarnitineClaudio De Simone (PDF, 578 KB)Department of Experimental Medicine, University of L'Aquila, Rome, Italy
The human immunodeficiency virus (HIV) causes a decline in the number of lymphocytes, resulting in acquired immune deficiency syndrome (AIDS). Antiretroviral agents, used to treat HIV-infection, may cause secondary L-carnitine deficiency. However, the molecular mechanisms implicated in the pathogenesis of HIV-associated carnitine deficiency are poorly understood. Preliminary research suggests that supplementation with carnitine may slow lymphocyte apoptosis, which in turn may slow the progression of HIV infection. L-Carnitine also inhibits production of ceramide, which is elevated in patients with AIDS, because of a lipid imbalance in cells. Ceramide is a ubiquitous second messenger that modulates cell differentiation, proliferation, survival, and apoptosis. Acetyl-L-Carnitine for the Treatment of Lipoatrophy in HIV-Infected Patients Taking Antiretroviral Drugs Mariana Gerschenson (PDF, 862 KB)Division of Heart and Vascular Diseases, NHLBI/NIH, Bethesda, Maryland
HIV lipoatrophy is a syndrome characterized by alterations in the distribution of fat tissue, with depletion of fat in the face, arms, and legs, and an accumulation of fat on the back of the neck, and in the abdominal visceral area. Hyperlipidemia and insulin resistance often accompany this syndrome. Mitochondrial changes play a role in the pathogenesis of HIV lipoatrophy. Supplementation of HIV-infected patients with mitochondrial co-factors, such as co-enzyme Q-10 and acetyl L-carnitine, is being evaluated in an NIH-funded study. Preliminary clinical chemistry data from this study suggest that this intervention is positively affecting mitochondrial metabolism.Session 6: New Perspectives in Carnitine Research
Chair: George P. Chrousos, Chief, Pediatric and Reproductive Endocrinology Branch, NICHD, NIH, Bethesda, MarylandCarnitine, a Nutritional Modulator of the Glucocorticoid ReceptorSalvatore Alesci (PDF, 702 KB)CNE/NIMH & PREB/NICHD, NIH, Bethesda, Maryland
Glucocorticoids help balance the effects of insulin; they affect metabolism and exert anti-inflammatory and immunosuppressive effects. Animal and human studies suggest that pharmacological doses of L-carnitine may mimic some glucocorticoid actions, such as their immunomodulatory effects. The ability of L-carnitine to activate glucocorticoid receptor alpha (GR ) may account for these glucocorticoid-mimicking effects. In-vitro studies demonstrate that L-carnitine competes with dexamethasone (a glucocorticoid) for binding to the GR .These preliminary studies suggest that L-carnitine may exert glucocorticoid-like immunomodulatory effects without the concomitant deleterious effects on bone. Effects of Carnitine on Thyroid Hormone Action Salvatore Benvenga (PDF, 381 KB)Cattedra di Endocrinologia, University of Messina School of Medicine, Messina, Italy
Animal studies suggest that carnitine may affect thyroid hormone homeostasis. Supplementing hyperthyroid patients with carnitine resulted in an improvement in symptoms without decreasing serum thyroid hormone (TH) levels, suggesting that these effects result from carnitine acting as a peripheral antagonist of TH rather than by directly inhibiting thyroid gland function. This theory was tested in recent studies to determine whether carnitine acts by inhibiting TH entry into the cells and nucleus, by inhibiting TH binding to nuclear receptors, or by affecting TH efflux from cells. The data suggest that carnitine acts by inhibiting TH entry into the cell nucleus. One implication of these findings, if confirmed, is that carnitine may have the potential for preventing osteoporosis in post-menopausal women who depend on TH suppressive therapy for the management of thyroid cancer.Carnitine and Cancer Ricardo A. Cruciani (PDF, 123 KB)Beth Israel Medical Center, Department of Pain Medicine and Palliative Care, New York, New York
Fatigue is a commonly reported symptom in cancer patients, resulting from chemotherapy, radiation treatment and poor nutritional status. In addition, a deficiency of carnitine is reported in these patients. Supplementation with carnitine resulted in improvement of fatigue, as evidenced in NIH-funded randomized controlled trails. Secondary outcomes included reduced depression, and overall improvement in the quality of life and performance status.Carnitine and Male InfertilityMarc R. Blackman (PDF, 250 KB)NCCAM, NIH, Bethesda, Maryland
Studies suggest that sperm count, motility, and maturation are related to epididymal-free carnitine concentrations. Supplementation with carnitine improved sperm quality and/or quantity in testes of mice exposed to physical insults, and in men with idiopathic oligoasthenospermia. These benefits are possibly due to increased mitochondrial fatty acid oxidation resulting in improvement in motility of epididymal sperm. The anti-apoptotic properties of carnitine in the testis are likely to contribute to these beneficial effects, but this hypothesis needs further investigation. L-Carnitine Ameliorates Vascular Dysfunction Caused by Elevated Free Fatty AcidsHelmet Steinberg (PDF, 119 KB)Indiana University School of Medicine, Indiana
Obesity and type 2 diabetes are characterized by impaired vascular endothelial function, an early step in the development of atherosclerotic disease. Elevated free fatty acid levels, decreased free fatty acid oxidation, and decreased carnitine levels characterize obesity and type 2 diabetes. As carnitine has been reported to exhibit vasoprotective properties, it may alleviate free fatty acid induced vascular dysfunction. In lean and obese individuals, oral carnitine supplementation exerted protective effects on the vasculature as measured by improved leg blood flow. This effect is mediated in part through improved release or action of nitric oxide a potent vasodilator. Summary and Future DirectionsPanel Discussion
Moderator: George P. Chrousos, NICHD, NIH
Bruce N. Ames, Paul Coates, Menotti Calvani, Charles Stanley
Many health benefits have been attributed to administration of carnitine. These include as a drug in the treatment of primary and secondary carnitine deficiency syndromes, and as a dietary supplement to aid weight loss, improve exercise performance, and enhance a sense of well-being. Further research is needed to elucidate the mechanisms by which carnitine acts in each of these conditions, and to prove whether carnitine, taken as a dietary supplement, is beneficial in individuals experiencing physical and psychological stress and during pregnancy. Designing the types of studies to prove benefits as a dietary supplement is challenging, as sensitive methods to measure subtle effects are lacking and large numbers of subjects are likely to be needed to demonstrate significant effects.
While the evidence of benefit in the treatment of primary and secondary systemic carnitine deficiency syndromes were highlighted during the conference, no major negative/toxic effects were attributed to carnitine supplementation. A review of the literature suggests that at doses of around 3,000 mg/day carnitine may cause a "fishy" body odor. Moreover, there are known interactions with drugs, e.g. pivalate conjugated antibiotics. Concluding RemarksPaul Coates(PDF, 575 KB)ODS, NIH, Bethesda, Maryland