L-Carnitine

By the CAM Cancer Collaboration | 29. Apr 2016

Abstract and key points
What is it?
Does it work?
Is it safe?
Evidence tables
References
Photo: Mostphotos.com

                     Photo: Mostphotos.com

This summary is currently being updated. The version published here was last updated in January 2015.

Description 

Carnitine is the generic term for a compound occurring naturally in humans, most animals, plants and microorganisms. It is part of the group of compounds that includes acetyl-L-carnitine and propionyl-L-carnitine. Most of the body’s carnitine is located within skeletal muscles, where it is critical for the supply of energy by the beta-oxidation of fatty acids. It also plays an important role in the stress response by modulating inflammatory and oxidative processes.

Efficacy

Fatigue: There is evidence from four randomized controlled trials (RCTs) indicating that L-carnitine does not reduce cancer-related fatigue in patients with advanced cancer.

Anorexia-cachexia syndrome: There is weak evidence from one small RCT and one uncontrolled study to show that L-carnitine has a positive influence on cancer anorexia-cachexia syndrome and 

Erectile dysfunction: There is evidence that acetyl-L-carnitine or propionyl-L-carnitine could be of help in reducing erectile dysfunction after prostatectomy.

Chemotherapy-induced peripheral neuropathy (CIPN): There is also weak evidence from two uncontrolled studies that acetyl-L-carnitine is effective in the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Evidence concerning the prevention of CIPN through acetyl-L-carnitine is contradictory, and findings from the most recent trial introduce a note of caution because it appears possible that acetyl-L-carnitine could even increase CIPN.

Cardiotoxicity: There is weak evidence that L-carnitine does not protect against anthracyclin-induced cardiotoxicity, and that it reduces cardiac side effects from interleukin-2.

Safety

The available clinical data suggest that L-carnitine is well tolerated and has been safely used in clinical trials at doses from 250mg to 6g per day for up to six months. Interactions with thyroid medications have been reported.

Citation

Renner P, Horneber M, CAM Cancer Collaboration. L-Carnitine [online document], Apr 29, 2016

Document history

Latest update: April 2016

Next update due: April 2019

L-carnitine (LC) is a naturally occurring compound which is present in humans, most animal species, numerous microorganisms and plants1. Together with its short-, medium- and long-chain esters, collectively referred to as acylcarnitines, LC forms the major component of the body’s carnitine pool. Other carnitine compounds include acyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC).

The vital metabolic functions of LC are to facilitate the transport of fatty acids (acyl groups) as acylcarnitines across the mitochondrial membrane for beta-oxidation, to maintaining adequate mitochondrial levels of free coenzyme A and to buffer excess acetyl-coenzyme A2. Further functions are: regulation of apoptosis and inflammation, protection from free radicals and modulation of proteins, cellular stress response and gene expression3-6.

Humans obtain LC both from endogenous synthesis and their diet. Meat, fish and dairy products are rich in LC and therefore valuable dietary sources; a well-balanced Western diet provides about 100-300mg LC per day7. However, in healthy adults with a balanced diet not all of the consumed LC is absorbed intestinally because the body is capable of synthesizing the amount it requires.

Ratios of tissue-to-plasma levels of LC and ALC are high, with a hundredfold difference between concentrations in skeletal muscle and blood plasma. Blood plasma contains both free (~80%) and esterified LC, usually in the form of ALC (20%) and plasma levels of total (free + esterified) LC are kept within narrow limits (40-50 micromole/L in healthy adults)8,9.

Circulating LC is excreted via the kidneys as LC or ALC. Renal tubules contain a highly efficient LC transport system that re-absorbs more than 98% of the LC in the glomerular filtrate. This mechanism is effective in conserving LC body stores even during LC-poor diets. If tubular reabsorption is affected by kidney disease, or inhibited by other compounds or drugs, the increased urinary loss can result in depletion of LC body stores8.

Scientific and other names

Carnitine was named from the Latin word for flesh (‘carno’) because it was first discovered in muscle tissue. Carnitine is a trimethylated amino acid and its chemical name is (3R)-3-hydroxy-4-(trimethylazaniumyl) butanoate (IUPAC). Carnitine contains a chiral centre and exists in two enantiomeric forms. L-carnitine is the biologically active enantiomer of carnitine. Other names used include: levocarnitine, carnitor, carnitene, karnitin and vitamin BT.

Ingredients

The majority of carnitine supplements contain LC. However, compounds containing the esterized forms ALC and PLC are also available over the counter.

Application and dosage

As LC is not regarded as an essential nutrient, no values for dietary reference intake or recommended daily allowance have been set. For supplementation or pharmacological purposes, LC is available as capsules, tablets or powder for oral use and as solutions for intravenous administration. Typical doses investigated in clinical trials have ranged from 250mg to 6g per day.

History/providers

Carnitine was discovered in 1905, isolated from muscle tissue1. Its chemical structure and major physiological functions were elucidated in the 1920s–1950s and investigations from the 1960s onwards have  led to the uncovering of its biosynthetic pathway, transport mechanisms and deficiency syndromes10. Today, leading manufacturers use prokaryotic biotransformation processes analogous to the natural biosynthetic pathway of carnitine, which yield pure LC with high efficiency11.

Claims of efficacy and alleged indications

Supplementation with LC is claimed to protect organs from chemo- and radiotherapy-related toxicities and to counteract cancer-related fatigue (CrF)and cancer anorexia-cachexia syndrome (CACS).

Mechanisms of action

The following explanations for the molecular mechanisms of action of LC are currently under discussion:

  1. Results from animal studies indicate that cancer-related cachexia is associated with liver-acinus lipid-metabolism zonation and decreased activity of carnitine palmitoyl transferases (CPT I and CPT II)12.Signs of cachexia have been found to be ameliorated in mice by modulating the expression and activity of CPTs and by regulating cytokines13,14. This is in line with findings that malnourished and cachectic patients have reduced plasma concentrations and stores of carnitine in the body15-18. However, observations in carnitine-deficient patients with lower carnitine stores suggest that these did not affect resting energy expenditure or total food intake19.
  2. Long-chain fatty acids are the most energy-rich substrates for beta-oxidation, and increased skeletal muscle LC content has been reported to delay muscular fatigue in rats20.It could be speculated that increases in ALC levels would have a significant impact on energy production, thus reducing fatigue.
  3. Findings in rats suggest that ALC could protect nervous tissue from chemotherapy-induced toxicity, through protein kinase C-related signalling pathways, by modulating the activities of nerve growth- and glial-derived neurotrophic factors21,22, and by protecting the mitochondria of peripheral nerves23.
  4. Animal studies also suggest that LC and PLC could decrease the duration and severity of radiation-induced mucositis because of their capacity to scavenge reactive oxygen species, activate antioxidant enzymes and protect DNA from cleavage24,25.
  5. There is evidence from rats that carnitine deficiency might aggravate carboplatin nephropathy26 and that patients with decreased dietary carnitine uptake develop carnitine deficiency when treated repeatedly with chemotherapy, including platinum derivatives27,29.
  6. There is evidence from two mouse models with carcinogen-induced cancers that dietary carnitine might inhibit the development of precancerous and neoplastic lesions30,31.

Prevalence of use

There are no data available on the prevalence of use of carnitine in cancer patients.

Legal issues

In the USA,LC is approved by the Food and Drug Administration for the treatment of carnitine deficiencies and according to the Office of Dietary Supplements, LC and ALC are approved dietary supplements7. In the EU,LC and PLC are approved for use in foodstuffs for particular nutritional uses51.

Description of included studies 

Supportive care

Please see Table 1 for details of clinical trials of LC, ALC and PLC.

Cancer-related fatigue                            

There is evidence from four recent randomized trials (RCTs), involving >800 participants with sufficiently robust measures of CrF that LC does not reduce moderate to severe CrF35-37 or that ALC prevents from CrF occurring during taxane-based chemotherapy38. These findings contradict those from several uncontrolled studies suggesting that L-carnitine (LC) might help against CrF32-34.

Cancer anorexia-cachexia syndrome

There is evidence that LC has beneficial effects on parameters related to CACS, based on the results from one RCT (n=72)36 and a prospective, uncontrolled study including 12 patients with advanced cancers32.

Sexual dysfunction

The evidence that ALC and PLC could prevent sexual dysfunction in patients after prostatectomy comes from one RCT39 which has been included and assessed in a Cochrane review on the effectiveness of interventions for sexual dysfunction. The review authors conclude that: ‘(...)there is some evidence suggestive that PDE5 [phosphodiesterase-inhibitor-5] inhibitors are more effective in combination with acetyl-L-carnitine and propionyl-L-carnitine’40.

Chemotherapy-induced peripheral neuropathy

There is evidence from two prospective, uncontrolled studies including 52 patients with different grades of CIPN that ALC is beneficial in the treatment of paclitaxel- and cisplatinum-induced peripheral neuropathy41,42.

Evidence that ALC or LC might protect from CIPN comes from two RCTs and is contradictory. The findings from the most recent trial, including 409 women receiving adjuvant taxane-containing chemotherapy, introduce a note of caution in that there are indications that ALC could even increase CIPN38. The author of a review mentions, however, an unpublished ‘double-blind, placebo-controlled, multicentre trial on 119 cancer patients treated with taxol alone or in combination with other neurotoxic or non-neurotoxic drugs’ in which ‘significant action of AL-carnitine [Acetyl-L-carnitine] in improving vibratory sensation in patients with CIPN, compared with placebo’ was found43.

Cardiotoxicity

Waldneret al. found no evidence that LC protects against anthracyclin-related cardiotoxicity in an RCT involving 40 lymphoma patients44, while Lissoniet al. found evidence that LC prevented cardiac adverse effects when high-dose interleukin-2 was used in an RCT with 30 patients45.

The use of LC is regarded as ‘Likely safe when used orally and appropriately and when used parenterally as an FDA-approved prescription medicine’46. Oral LC has been used safely in children for up to 2 months and intravenously in preterm infants. For pregnant women, there is insufficient reliable information available to date. Although LC is secreted in breast milk, use during breast-feeding is regarded as safe because supplemental doses of LC have been administered to children in formula diets with no reported adverse effects46. Clinical trials lasting from four weeks to six months have used amounts  of LC from under 1g up to 6g per day without any apparent ill effects.

Adverse effects

In the studies discussed above, LC used orally or intravenously has been less frequently associated with nausea, insomnia, vomiting and gastrointestinal upset of minor intensity.

Contraindications

Patients using thyroid medications should not take LC unless supervised by a physician. Individuals with low or borderline-low thyroid levels should avoid taking supplemental LC because it might impair the action of thyroid hormones47.

Interactions

It has been observed that long-term treatment with ementine, pivalic acid and the anticonvulsant valproic acid leads to secondary carnitine deficiency. Histological findings of an animal study in mice with Ehrlich tumour indicate that combining ALC with mitoxantrone might be inappropriate48.

Quality issues

Supplements containing D-carnitine or dl-racemates should be avoided because D-carnitine can interfere with LC membrane transport, thus increasing the risk of LC deficiency49,50.

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  21. Di Cesare ML, Ghelardini C, Toscano A, Pacini A, Bartolini A. The neuropathy-protective agent acetyl-L-carnitine activates protein kinase C-gamma and MAPKs in a rat model of neuropathic pain. Neuroscience. 2010;165(4):1345-52.
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  23. Jin HW, Flatters SJ, Xiao WH, Mulhern HL, Bennett GJ. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Exp Neurol. 2008;210(1):229-37.
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  25. Ucuncu H, Ertekin MV, Yoruk O, Sezen O, Ozkan A, Erdogan F, et al. Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced oral mucositis and myelosuppression: a controlled study in a rat model. J Radiat Res. 2006;47(1):91-102.
  26. Arafa HM. Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids. Toxicology. 2008;254(1-2):51-60.
  27. Haschke M, Vitins T, Lude S, Todesco L, Novakova K, Herrmann R, et al. Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs. Nephrol Dial Transplant. 2010;25(2):426-33.
  28. Heuberger W, Berardi S, Jacky E, Pey P, Krahenbuhl S, Heuberger W, et al. Increased urinary excretion of carnitine in patients treated with cisplatin. Eur J Clin Pharmacol. 1998;54(7):503-8.
  29. Mancinelli A, D'Iddio S, Bisonni R, Graziano F, Lippe P, Calvani M, et al. Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment. Cancer Chemother Pharmacol. 2007;60(1):19-26.
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  31. Dionne S, Elimrani I, Roy MJ, Qureshi IA, Sarma DR, Levy E, et al. Studies on the chemopreventive effect of carnitine on tumorigenesis in vivo, using two experimental murine models of colon cancer. Nutr Cancer. 2012;64(8):1279-87.
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