FactSHEET L- AND L-ACETYLCARNITINE

What is carnitine? 2.helping to decrease levels of lactic acid in the blood L-carnitine is an amino acid found in red meat 3.reducing higher-than-normal levels of and acetyl-L-carnitine is another form of this cholesterol and/or triglycerides . Carnitine can be made in small quantities by the brain, liver and kidneys. 4.helping to maintain muscle growth Among other things, this amino acid plays a role in helping to release energy from fat by 1. To manage (nerve moving fats to power plants within cells where damage causing tingling, numbness or fats can be burnt as fuel. These cellular power burning in the hands, feet and legs) plants are called mitochondria and are Levels of carnitine in the blood are sometimes responsible for making the energy a cell needs lower in PHAs with peripheral neuropathy, to survive and function. particularly under the following conditions: Carnitine appears to have • damage from viral infections such as HIV properties and may also play a role in and CMV (cytomegalovirus) maintaining blood sugar levels. According to at least one study, people with HIV/AIDS • the use of “d” drugs such as d4T, ddI and (PHAs) can have normal levels of carnitine in ddC their serum (the fluid part of the blood) while • the use of some anti-cancer drugs and still having very low levels in the cells, where antibiotics carnitine is needed. • abuse In PHAs whose health has improved because • diabetes of highly active antiretroviral therapy (HAART), carnitine levels may not return to normal. What the medications in the above list have When taken orally as a supplement, only a in common is that they can damage the relatively small amount—between 5% and energy-producing parts of nerve cells—the 18%—of carnitine is absorbed. mitochondria. Injured mitochondria cannot supply sufficient energy and nerves begin to malfunction and can die. Nerves in the feet, Why do PHAs use this legs and hands, particularly in the skin supplement? covering those body parts, appear to be especially susceptible to PN. Some researchers Carnitine has many potential uses, including have noticed that PHAs with PN can develop the following: abnormal sweating, suggesting that nerves in 1.helping to heal damaged nerves—peripheral sweat glands can also be affected. neuropathy (PN) One formulation of carnitine, acetyl-L-carnitine

CATIE FactSHEET Carnitine, page 1 of 6 (ALCAR), may play a role in the management of Overall, this study goes a long way toward PN. This compound helps mitochondria function helping researchers explore the role of and also appears to enhance the effect of a carnitine, particularly ALCAR, as part of the chemical that helps nerves grow—nerve growth management of PN. factor. Two randomized, placebo-controlled studies Researchers in England conducted an extensive using ALCAR 500 mg/day or 1,000 mg/day study of ALCAR in PHAs with peripheral have also found it to be beneficial in the neuropathy. Their findings revealed that most management of PN in HIV negative people PHAs showed some degree of recovery from with diabetes. nerve damage after taking ALCAR 1.5 grams twice daily for up to 2¾ years. 2. To help reduce lactic acid levels in the blood Seventy-six percent of participants had significantly reduced pain. Because this was not One of the complications that can occur in a controlled clinical trial comparing ALCAR to a users of a class of anti-HIV drugs called placebo or another substance, researchers nucleoside analogues, is the development of cannot be certain that the reduction in pain higher-than-normal levels of lactic acid. If was indeed caused by ALCAR. To clarify this levels become very high, the following signs/ issue, placebo-controlled studies of ALCAR are symptoms may occur as part of a condition taking place in the European Union and in called lactic acidosis: Vancouver, British Columbia. • unexpected tiredness In the British study, analyses of skin samples • abdominal pain taken during the clinical trial found that after six months of ALCAR use, nerve fibres were • swollen, fatty liver undergoing re-growth. The longer participants • shortness of breath took the supplement, the greater the re-growth. • nausea and/or vomiting Nerve fibres are slow-growing so it clearly takes many months, perhaps even years, for the The following blood tests help identify lactic damage from PN to heal. acidosis: There were no significant changes to CD4+ and • lactate levels of 5 mmol/L or greater CD8+ cells or viral load measures during the • bicarbonate levels of 20 mmol/L or lower study. Anecdotal reports suggest that L-carnitine may The research team speculates that ALCAR may play a role in helping PHAs to recover from have helped nerves for the following reasons: lactic acidosis. In a pilot study of six PHAs who were extremely ill and who had high levels • Carnitine has antioxidant properties, possibly of lactic acid in their blood from drug-related protecting nerve cells from the toxicity of side effects, researchers gave them intravenous nucleoside analogues. L-carnitine at doses between 50 mg and 100 • By improving the transport of fats and sugar, mg/kg of body weight per day. Despite this carnitine may have helped cells become more treatment, only three of the participants energetic and active, perhaps stimulating survived and recovered from lactic acidosis. their recovery. Other researchers have intervened at earlier • Carnitine could have helped nerve regrowth stages of lactic acidosis with oral supplements and repair by enhancing the effects of nerve of B and L-carnitine with successful growth factor. results. • PHAs with PN have been found to have decreased levels of ALCAR in their blood and the supplement could have reversed this. CATIE FactSHEET Carnitine, page 2 of 6 3. To reduce high levels of cholesterol and/or L-carnitine twice daily for three months. triglycerides in the blood However, this supplement did not prevent fat loss, though cholesterol but not triglyceride Having higher-than-normal levels of lipids— levels fell significantly. Researchers at the cholesterol and triglycerides— in the blood University of Modena in Italy are planning a increases the risk of cardiovascular disease. clinical trial of acetyl-l-carnitine at a dose of 3 In a small, controlled trial of HIV positive grams daily to assess any impact on the HIV people, carnitine caused triglyceride levels to lipodystrophy syndrome. They have decided drop significantly after two weeks at a dose of to do this because they have previously six grams daily. However, this study was done conducted lab experiments with cells, nukes in 1993, when AZT was the only antiretroviral and ALCAR. In doing those experiments, they drug being used. found that this supplement was able to partially In 2001, results of a pilot study in Montreal prevent some of the damage caused by d4T were released. L-carnitine at a dose of 3 grams and AZT (Giovanni Guaraldi MD, personal daily was used by 16 PHAs who were also communication). taking HAART. Triglyceride levels decreased For further information about lipodystrophy and significantly within the first month and by the ways to manage HIV drug-related side effects, end of the study had deceased by about 35%. please see CATIE’s Practical Guide to By the end of the study, 70% of participants Managing Drug Side Effects at http:// had their triglyceride levels return to the normal www.catie.ca/sideeffects_e.nsf. range. In the same year, a German study found that Availability L-carnitine at a dose of 1 gram twice daily for three months lowered cholesterol but not Carnitine is made by the Sigma-Tau company, triglyceride levels in 12 PHAs. in Italy, in two formulations: • L-carnitine 4. To avoid muscle wasting and fatigue • acetyl-L-carnitine Some HIV positive people use carnitine L-carnitine is sold under the brand name supplements to treat muscle wasting and Carnitor and is available by prescription in fatigue due to anti-HIV drugs. A 1994 study North America. Acetyl-L-carnitine (ALCAR) is of 21 men with AZT-related myopathy (muscle sold under the brand name Nicetile in Italy wasting) showed that the men’s muscle tissue and some countries of the European Union. had been damaged and that lipids (fats) had Sigma-Tau does not appear to market ALCAR built up in the tissue. The study also showed in North America. In Canada and the United that the most badly damaged muscle had the States, some health food stores also sell lowest levels of carnitine. A test-tube study different brands and formulations of carnitine. done the same year suggested that carnitine All formulations of carnitine are expensive. supplements might improve AZT-related ALCAR is more often used in studies of myopathy, although no trials in HIV positive neuropathy and may be most useful for this people have been done to assess this condition. Both formulations of carnitine have compound’s impact on muscle wasting and been used in trials related to HIV, although fatigue. some HIV nutritional experts have suggested the acetyl form may be more useful. 5. To delay or minimize fat wasting The dose usually recommended for PHAs L-carnitine has been tested in Germany as a varies between 500 mg and 3,000 mg (3 potential treatment to stop the loss of fat that grams) a day. This can be divided into several can occur with the HIV lipodystrophy doses and taken with food. syndrome. Twelve PHAs were given 1 gram of

CATIE FactSHEET Carnitine, page 3 of 6 Side effects Drug interactions 1. Gastrointestinal Always tell your doctor and other members of your health care team about all the Nausea, vomiting and diarrhea may occur, medications—prescription and non- especially in people who take more than 4 prescription—herbs and supplements that you grams per day. are taking. Carnitine may interfere with the following drugs: 2. Neurological • drugs to treat or prevent blood clots— Seizures have been reported in some people acenocoumarol/nicoumalone (Sintrom) taking carnitine supplements, regardless of whether or not these people had seizures in • thyroid hormones the past. Credits 3. Thyroid hormones Author: Sean R. Hosein The hormones produced by the thyroid gland Reviewed by Matthias Banasch MD are called T3 (triiodothyronine) and T4 (thyroxine). Thyroid hormones help control the Created: 2006 body’s ability to produce energy and regulate Design: Renata Lipovitch its temperature. In lab experiments, L-carnitine blocks the ability of cells to respond to these hormones. In studies in HIV negative people, References: L-carnitine, at doses of 2 or 4 grams per day, Carnitor (levocarnitine). Product Monograph. Compendium of reduced thyroid hormone levels. We are not Pharmaceutical Specialties 2005. sure what effect lower doses of carnitine might Vaz FM and Wanders RJ. Carnitine biosynthesis in mammals. have on thyroid hormone levels. If thyroid Biochemical Journal 2002;361(Pt 3):417-429. hormone levels fall below normal, a range of De Simone C, Tzantzoglou S et al. L-carnitine deficiency in symptoms may develop, including the AIDS patients. AIDS 1992;6:203-5. following: De Simone C et al. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: Effect of oral L- • unexpected tiredness carnitine. AIDS 1994;8:655-660. • feeling cold Vilaseca MA, Artuch R, Sierra C, et al. Low serum carnitine in HIV-infected children on antiretroviral treatment. European • dry skin Journal of Clinical 2003;57(10):1317-1322. • muscle weakness Famularo G, De Simone C. Carnitine stands on its own in HIV infection treatment. Archives of Internal Medicine 1999 • forgetfulness and difficulty concentrating May;159:1143-4. • impaired hearing Evans AM and Fornasini G. of L-carnitine. Clinical Pharmacokinetics 2003;42(11):941-967. If you are taking carnitine supplements, your Famularo G, Moretti S et al. Acetyl-carnitine deficiency in doctor may wish to regularly monitor the health AIDS patients with neurotoxicity on treatment with antiretroviral of your thyroid gland. nucleoside analogues. AIDS 1997 Feb;11(2):185-90. Ilias I, Manoli I, Blackman MR, et al. L-Carnitine and acetyl- 4. Pregnancy L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. 2004; Carnitine has not been studied in pregnant 4(2-3):163-8. women. Therefore, the manufacturer suggests Sima AA, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves that carnitine only be used in this population pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized if it is clearly needed. placebo-controlled trials. Diabetes Care 2005;28(1):89-94.

CATIE FactSHEET Carnitine, page 4 of 6 Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a adverse drug reactions and lipodystrophy in HIV; 13-16 pathogenesis based treatment for HIV-associated antiretroviral November, 2005. Dublin, Ireland. Poster 84. toxic neuropathy. AIDS 2004;18(11):1549-1560. Vrouenraets SM, Treskes M, Regez RM, et al. Hyperlactataemia in HIV-infected patients: the role of NRTI-treatment. Antiviral Therapy 2002;7(4):239-244. Brinkman K, Vrouenraets S, Kauffmann R, et al. Treatment of nucleoside reverse transcriptase inhibitor-induced lactic acidosis. AIDS 2000;14(17):2801-2802. Carter RW, Singh J, Archambault C, and Arrieta A. Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to L-carnitine in a pediatric HIV-positive patient. AIDS Patient Care and STDs. 2004;18(3):131-134. Claessens YE, Cariou A, Monchi M, et al. Detecting life- threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Critical Care Medicine 2003;31(4):1042-1047. Muller DM, Seim H, Kiess W, et al. Effects of oral L-carnitine supplementation on in vivo long-chain fatty acid oxidation in healthy adults. Metabolism 2002;51(11):1389-1391. De Simone C, Tzantzoglou S et al. High-dose L-carnitine improves immunologic and and metabolic parameters in AIDS patients. Immunopharmacology and Immunotoxicology 1993;15(1):1-12. Loignon M and Toma E. L-Carnitine for the treatment of highly active antiretroviral therapy-related hypertriglyceridemia in HIV- infected adults. AIDS 2001;15(9):1194-1195. Mingrone G. Carnitine in type 2 diabetes. Annals of the New York Academy of Sciences 2004;1033: 1033:99-107. Myers C. Carnitine - updated. 1998 Feb. Available at: www.catie.ca/myers.nsf Myers C. Day L, Shikuma C and Gerschenson M. Acetyl-L-carnitine for the treatment of HIV lipoatrophy. Annals of the New York Academy of Sciences 2004;1033:139-46. Dalakas MC, Leon-Monzon MEL et al. Zidoudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Annals of Neurology 1994 April;35(4):482-7. Georges B, Galland S, Rigault C, et al. Beneficial effects of L- carnitine in myoblastic C2C12 cells. Interaction with zidovudine. Biochemical Pharmacology 2003;65(9):1483-1488. Mauss S and Schmutz G. L-Carnitine in the treatment of HIV- associated lipodystrophy syndrome. HIV Medicine 2001;2(1):59-60. Benvenga S, Amato A, Calvani M and Trimarchi F. Effects of carnitine on thyroid hormone action. Annals of the New York Academy of Sciences 2004;1033:158-67. Bachmann HU and Hoffmann A. Interaction of food supplement L-carnitine with oral anticoagulant acenocoumarol. Swiss Medical Weekly 2004;134(25-26):385. Ferraresi R, Troiano L, Roat E, et al. Protective effect of acetyl- l-carnitine on oxidative damage induced by antiretroviral drugs. Program and abstracts of the 7th International workshop on

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CATIE FactSHEET Carnitine, page 6 of 6