Compendium of the most significant studies with reference to properties, intake, effects.

Durazzo A, Lucarini M, Nazhand A, Souto SB, Silva AM, Severino P, Souto EB, Santini A. The Nutraceutical Value of Carnitine and Its Use in Dietary Supplements. Molecules. 2020 May 1;25(9):2127. doi: 10.3390/molecules25092127.

Abstract. Carnitine can be considered a conditionally essential nutrient for its importance in human physiology. This paper provides an updated picture of the main features of carnitine outlining its interest and possible use. Particular attention has been addressed to its beneficial properties, exploiting carnitine's properties and possible use by considering the main in vitro, in animal, and human studies. Moreover, the main aspects of carnitine-based dietary supplements have been indicated and defined with reference to their possible beneficial health properties.

Borum PR. Carnitine. Annu Rev Nutr. 1983;3:233-59. doi: 10.1146/annurev.nu.03.070183.001313. 

Abstract. Carnitine has a critical role in energy metabolism. Many of the functions of carnitine are not clearly elucidated and many of the regulatory mechanisms governing carnitine metabolism are ill-defined. Carnitine deficiency can be life threatening but may be resolved with carnitine supplementation. Various groups of individuals in addition to those with the classical carnitine deficiency syndrome may require exogenous carnitine. Carnitine nutriture can no longer be ignored.

Gnoni A, Longo S, Gnoni GV, Giudetti AM. Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise? Molecules. 2020 Jan 1;25(1):182. doi: 10.3390/molecules25010182.

Abstract. l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement.

Bach AC. Carnitine in human nutrition. Z Ernahrungswiss. 1982 Dec;21(4):257-65. doi: 10.1007/BF02020743. 

Abstract. The oxidation of long-chain fatty acids is carnitine-dependent. Indeed, only when they are bound to carnitine, in the form of acyl-carnitines, do fatty acids penetrate into the mitochondria to be oxidized. To meet the need for carnitine, animals depend on both endogenous synthesis and an exogenous supply. A diet rich in meat supplies a lot of carnitine, while vegetables, fruits, and grains furnish relatively little. Although it has a low molecular weight and acts at low doses in a vital metabolic pathway, carnitine should not be considered a vitamin, but rather a nutritive substance. Indeed, it seems that the diet of the adult human need not necessarily furnish carnitine: the healthy organism, given a balanced nutrition (sufficiently rich in lysine and methionine), may well be able to meet all its needs. Furthermore, it seems that a reduction of the exogenous supply of carnitine results in a lowering of its elimination in the urine. However, dietary carnitine is more important during the neonatal period. The transition from fetal to extrauterine life is accompanied by an increased role of lipids in meeting energy needs. This change is accompanied by a rise in the body of the levels of carnitine, which is mainly supplied in the maternal milk. Finally, this review briefly surveys the illnesses in which a dietary carnitine supplement proves useful.

Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci. 2004 Nov;1033:92-8. doi: 10.1196/annals.1320.008. 

Abstract. Patients with peripheral arterial disease (PAD) who become symptomatic with claudication (approximately one-third of the population) have a marked impairment in exercise performance and overall functional capacity. Patients with claudication have a peak oxygen consumption measured during graded treadmill exercise testing that is 50% of that in age-matched normal subjects, and also report great difficulty in walking relatively short distances, even at a slow walking speed. The reduced walking capacity is associated with impairment in activities of daily living and quality of life. Thus, claudication is highly limiting to the physical functioning of daily activities. Improving mobility and improving the reduced quality of life are therefore major goals of treatment. Patients with PAD develop metabolic abnormalities in the skeletal muscles of the lower extremity. These abnormalities include impairment in ischemic muscle mitochondrial electron transport chain activity and accumulation of intermediates of oxidative metabolism (acylcarnitines). Patients with the greatest accumulation of muscle acylcarnitines have the most impaired exercise performance. Thus, claudication is not simply the result of reduced blood flow, and alterations in skeletal muscle metabolism are part of the pathophysiology of the disease. L-carnitine and propionyl-L-carnitine may improve the metabolism and exercise performance of ischemic muscles. L-carnitine in a dose of 2 grams twice daily improved treadmill performance, but propionyl-L-carnitine (an acyl form of carnitine) was more effective than L-carnitine in improving treadmill walking distance. In two multicenter trials of a total of 730 patients, initial and maximal treadmill walking distance improved more with propionyl-L-carnitine than placebo. The drug also improved quality of life and had minimal side effects as compared with placebo. Propionyl-L-carnitine has not been approved for use in the United States.

Steiber A, Kerner J, Hoppel CL. Carnitine: a nutritional, biosynthetic, and functional perspective. Mol Aspects Med. 2004 Oct-Dec;25(5-6):455-73. doi: 10.1016/j.mam.2004.06.006. 

Abstract. Carnitine status in humans is reported to vary according to body composition, gender, and diet. Plasma carnitine concentration positively correlates with the dietary intake of carnitine. The content of carnitine in foodstuff is based on old and inadequate methodology. Nevertheless, dietary carnitine is important. The molecular biology of the enzymes of carnitine biosynthesis has recently been accomplished. Carnitine biosynthesis requires pathways in different tissues and is an efficient system. Overall biosynthesis is determined by the availability of trimethyllysine from tissue proteins. Carnitine deficiency resulting from a defect in biosynthesis has yet to be reported. The role of carnitine in long-chain fatty acid oxidation is well defined. Recent evidence supports a role for the voltage-dependent anion channel in the transport of acyl-CoAs through the mitochondrial outer membrane. The mitochondrial outer membrane carnitine palmitoyltransferase-I in liver can be phosphorylated and when phosphorylated the sensitivity to malonyl-CoA is greatly decreased. This may explain the change in sensitivity of liver carnitine palmitoyltransferase-I observed during fasting and diabetes. Recently reported data clarify the role of carnitine and the carnitine transport system in the interplay between peroxisomes and mitochondrial fatty acid oxidation. Lastly, the buffering of the acyl-CoA/CoA coupled by carnitine reflects intracellular metabolism. This mass action effect underlies the use of carnitine as a therapeutic agent. In summary, these new observations help to further our understanding of the molecular aspects of carnitine in medicine.

Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr. 2000 Aug;72(2 Suppl):618S-23S. doi: 10.1093/ajcn/72.2.618S. 

Abstract. Carnitine is an endogenous compound with well-established roles in intermediary metabolism. An obligate for optimal mitochondrial fatty acid oxidation, it is a critical source of energy and also protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Carnitine homeostasis is affected by exercise in a well-defined manner because of the interaction of the carnitine-acylcarnitine pool with key metabolic pathways. Carnitine supplementation has been hypothesized to improve exercise performance in healthy humans through various mechanisms, including enhanced muscle fatty acid oxidation, altered glucose homeostasis, enhanced acylcarnitine production, modification of training responses, and altered muscle fatigue resistance. Available experimental clinical studies designed to assess the effect of carnitine on exercise metabolism or performance in healthy humans do not permit definitive conclusions to be drawn. In the aggregate, however, these studies suggest that carnitine supplementation does not improve maximal oxygen uptake or metabolic status during exercise in healthy humans. Carnitine administration for

Malaguarnera G, Catania VE, Bonfiglio C, Bertino G, Vicari E, Malaguarnera M. Carnitine Serum Levels in Frail Older Subjects. Nutrients. 2020 Dec 19;12(12):3887. doi: 10.3390/nu12123887. 

Abstract. Frailty is an expression that reconciles and condenses loss of autonomy, both physical and cognitive decline and a wide spectrum of adverse outcomes due to aging. The decrease in physical and cognitive activity is associated with altered mitochondrial function, and energy loss and consequently morbidity and mortality. In this cross-sectional study, we evaluated the carnitine levels in frailty status. The mean serum concentrations of total carnitine (TC) were lower in frail elderly subjects than in prefrail ones (p = 0.0006), higher in frail vs. robust subjects (p < 0.0001), and higher in prefrail vs. robust subjects (p < 0.0001). The mean serum concentrations of free carnitine (FC) were lower in frail elderly subjects than in prefrail ones (p < 0.0001), lower in frail vs. robust subjects (p < 0.0001) and lower in prefrail vs. robust subjects (p = 0.0009). The mean serum concentrations of acylcarnitine (AC) were higher in frail elderly subjects than in prefrail ones (p = 0.054) and were higher in pre-frail vs. robust subjects (p = 0.0022). The mean urine concentrations of TC were lower in frail elderly subjects than in prefrail ones (p < 0.05) and lower in frail vs. robust subjects (p < 0.0001). The mean urine concentrations of free carnitine were lower in frail elderly vs. robust subjects (p < 0.05). The mean urine concentrations of acyl carnitines were lower in frail elderly subjects than those in both prefrail (p < 0.0001) and robust subjects (p < 0.0001). Conclusion: high levels of carnitine may have a favorable effect on the functional status and may treat the frailty status in older subjects.

Zammit VA, Ramsay RR, Bonomini M, Arduini A. Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1353-62. doi: 10.1016/j.addr.2009.04.024.

Abstract. Carnitine is important for cell function and survival primarily because of its involvement in the multiple equilibria between acylcarnitine and acyl-CoA esters established through the enzymatic activities of the family of carnitine acyltransferases. These have different acyl chain-length specificities and intracellular compartment distributions, and act in synchrony to regulate multiple aspects of metabolism, ranging from fuel-selection and -sensing, to the modulation of the signal transduction mechanisms involved in many homeostatic systems. This review aims to rationalise the extensive range of experimental and clinical data that have been obtained through the pharmacological use of L-carnitine and its short-chain acylesters, over the past two decades, in terms of the basic biochemical mechanisms involved in the effects of carnitine on the various cellular acyl-CoA pools in health and disease.

Pescosolido N, Imperatrice B, Karavitis P. The aging eye and the role of L-carnitine and its derivatives. Drugs R D. 2008;9 Suppl 1:3-14. doi: 10.2165/0126839-200809001-00002. 

Abstract. The majority of ocular pathologies originate from a functional deterioration of intraocular tissues. This age-related deterioration often occurs as a result of changes within the eye. There is growing interest in the role of natural or synthetic compounds, such as carnitine, for blocking, or slowing, the progress of this deterioration. L-carnitine and its derivatives are involved in numerous physiological reactions, including sugar aerobic metabolism, oxidative phosphorylation, fatty acid oxidation and osmosis. While carnitine levels in human ocular tissue are unknown, animal studies indicate that carnitine is differentially distributed within the eye with the highest concentrations reported in the iris, ciliary body and the choroid-retina. In patients with age-related macular degeneration (AMD), acetyl-L-carnitine improved four parameters of visual function, including visual field mean defect, visual acuity, foveal sensitivity and ocular fundus alterations. L-carnitine has also demonstrated antioxidant properties in animal models of oxidative damage. This article reviews the potential use of L-carnitine and its derivatives in age-related ocular pathologies, such as AMD, cataract, glaucoma and dry eye syndrome.

Nałecz KA, Miecz D, Berezowski V, Cecchelli R. Carnitine: transport and physiological functions in the brain. Mol Aspects Med. 2004 Oct-Dec;25(5-6):551-67. doi: 10.1016/j.mam.2004.06.001. 

Abstract. Carnitine (4-N-trimethylammonium-3-hydroxybutyric acid), a compound necessary for a transfer of fatty acids for their oxidation within the cell, accumulates in brain although beta-oxidation of fatty acids is very low in neurons. Carnitine accumulates to lower extent in the brain than in peripheral tissues and the mechanism of its transport through the blood-brain barrier is discussed, with the involvement of two transporters, OCTN2 and B(0,+) being presented. A limitation by the blood-brain barrier of carnitine supply for the brain and the mechanism of its transport to neural cells by a protein belonging to neurotransmitters' transporters superfamily is further discussed. Due to the beneficial effects of administration of acetylcarnitine in case of patients with dementia, the role of this acylcarnitine is presented in the context of neuronal cell metabolism and the role of acetylcarnitine in the synthesis of acetylcholine. The roles of long-chain acyl derivatives of carnitine, in particular palmitoylcarnitine, responsible for interaction with the membranes, lipids acylation and specific interactions with proteins have been summarized. Stimulation of protein palmitoylation and a possibility of changing the acylation status of G proteins is described, as well as interaction of palmitoylcarnitine with protein kinase C. Diminished interaction of the isoform delta of this kinase with GAP-43 (B-50, neuromodulin), whose expression increases upon accumulation of either carnitine or palmitoylcarnitine points to a possible regulation of differentiation by these compounds and their role in neuroregeneration.