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L-Carnitine Monogra

Chemical Structure of L-Ca rnitine

L-Carnitine

IntroductionA trimethylated amino acid, roughly sim

in structure to choline, L-camitine is a cofactor required for transformation of free long-chain fatty acids i

acylca rnitines, and for their subsequent transport into the m itochondrial matrix, where they unde rgo b eta-oxidat

for cellular energy production. Conditions that appear to benefit from exogenous supplementation of L-carni

include anorexia, chronic fatigue, cardiovascular disease, diphtheria, hypoglycemia. male infertility, tnuscular m

opathies. and Rett syndrome. Preterm infants, dialysis patients, and HIV-positive individuals seem to be prone t

deficiency ofL-carnitine and benefit from supplementation.

Although discovered in 1905, the crucial role of L-camitine in metabolism was not elucidated until 1

and its deficiency was not described until 1972. The most significant source of L-carnitine inhuman nutrition

meat, although humans can synthesize L-camitine from dietary am ino acids.

Biochemistry and Pharm acokineticsSynthesis of carnitine begins with methylation of the amino acid L-lysine by S-adenosylmethionine

(SAMe). Magnesium, vitamin C, iron, vitamins B3 and B6. and alpha-ketoglutarate - along with the cofactors

sponsible for creating SA Me (m ethionine. folic acid, vitamin B I2 . and b et ai ne )- ar e all required for endogeno

carnitine synthesis.

Evidence indicates L-camitine is absorbed in the intestine by a combination of active transport and passive diffusion.' Reports of bioavailability following an oral dose ha ve varied substantially, with estima tes as lowas 16-18 percent-' and as high as 54-87 percent.""'^

Oral supplementation of L-camitine in individual dosages greater than 2 g appears to offer no advantag

since the mucosal absorption of camitine appears to be saturated at about a 2-g dose.- Maximum blood concen-

tration is reached approximately 3.5 hours after an oral dose and slowly decreases, with ahalf-life of about 15hours."^ Elimination of carnitine occurs primarily through the kidneys.^

The heart, skeletal muscle, liver, kidneys, and epididymis have specific transport systems for camitine

that concentrate carnitine within these tissues. Despite evidence indicating increased levels of free carnitine and

carnitine m etabolites in the blood and urine following an oral dos e, no significant chang e in red blood cell carn

tine levels was noted in healthy su bjects, suggesting either a slow repletion of tissue stores of carnitine followin

an oral dose or a low capability to transport camitine into tissues under normal conditions.''

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L-Carnitine

Carnitine's primary mechanism of action

acylcarnitines for subsequent transport into the

Carnitine is involved in the tnetabolism of

energy** and the conversion of branched-

- valine, leucine, and isoleucine

into energy."^

Although L-carnitine is supplied exog-

Pre-temi infants are at risk for developing

Deficiency can result in cardiomyopathy,

Primary camitine deficiency, although rare,

or leth-

Secondary carnitine deficiency is not as rare

d is most commonly associated with dialysis in

and liver

Pathological manifestations of chronic defi-

of neutral lipid within

a disrup-

and an accum ulation of large ag-

Clinical Indications

AnorexiaCombined use of L-camitine and adenosyl-

cobalamin in patients with anorexia nervosa has been

shown to accelerate body weight gain, nomialize gas-

trointestinal function, decrease fatigue, and improve

physical pe rform ance ." '̂ Children with infantile an -

orexia responded to a combination of carnitine and

adenosylcobalamin with improved appetite.'''

Athletic PerformanceA clinical study reported improved running

speed and decreased average oxygen consump-

tion and heart rate following prolonged L-camitinesupplementation,'^ while other researchers reported

increased maximal oxygen uptake and decreased

plasma lactate when L-carnitine was supplemented

acutely one hour prior to beginning exercise." A

small study on L-camitine"s effect on high-repetition

squat exercise found significant benefit from 2 g car-

nitine daily compared to placebo on blood param eters

of muscle recovery - myoglobin, creatine kinase. and

malondialdehyde."* In contrast, other research has

shown no ergogenic effects of either chronic or acute

L-camitine supplementation.'"-'

Cardiovascular DiseaseAngina and Ischemia

L-camitine (oral doses ranging from 900-3.000 mg daily) has been shown tomoderately im-prove exercise tolerance and reduce ECG indices ofischemia in patients with stable angina. Estimatessuggest upward of 22 percent of subjects might be-come angina-free during supplementation periodsIncreasing benefits are often observed with longer

suppletnentation.-- -̂

Angina patients receiving L-carnitine haveexperieticed functional improvement, including a reduction in the number of premature ventricular con-tractions at rest, an increase inmaximal systolic ar-terial blood pressure, and a reduction in ST-segmentdepression during maximal effort. In addition, a con-com itant increase in the num ber of patients be longingto class I of the NYHA classification (as opposed toclasses II and III) and a reduction in the consu mptionof cardioactive drugs has been reported.-"

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L-Carnitine Monogra

In subjects with ischemia-induced NYHA II

or III cardiac insufliciency, L-carnitine supplementa-

tion {1 g three times daily for 120 days), in addition

lo the usual medications (digitalis, beta-blockers, cal-cium antagonists, nitrates), resulted in improvements

in exercise performance and hemodynamic parame-

ters. Benefits were maintained beyond the L-carnitine

supplementation period.-^

Peripheral Vascular DiseaseIn a double-b lind, crossove r study of sub jects

with peripheral vascular disease, walking distance

improved from anaverage of 174 minutes with pla-

cebo to 306 minutes with L-carnitine at a dose of2 g

twiee daily for three weeks.'** In healthy subjects, L-carnitine was found to inhibit fatty-acid induced en-

dothelial dysfunction intended tosimulate that seen

in obesity or type 2 diabetes.-'*

Cardiogenic ShockL-camitine supplementation during cardio-

genie shock improved metabolic acidosis and sur-

vival rate in hospitalized individuals.-^"-"

CardiomyopathyLong-term supplementation of L-carnitine

(2 g daily) for the treatment of heart failure caused

by dilated cardiomyopathy resulted in improvement

in survival rate, ejection fraction. Weber classifica-

tion, maximal time of cardiopulmonary exercise test,

peak VO, consumption, arterial and pulmonary biood

pressure, and cardiac output."-'^

Myocardial InfarctionFollowing a recent myocardial infarction

(MI), a marked reduction in mortality was observedwith 12-month supplementation of 4 g daily L-carni-

tine (1.2%) when compared to controls (12.5%). Sig-

nificant improvements were also noted in heart rate

and anginal attacks.^'' Additional research confirms a

benefit in terms of redueed mortality in individuals

given L-earnitine following MI.'^'^

HyperlipidemiaL-carnitine (2-3 g daily) resulted in impro

lipid profiles in individuals with hyperlipidemia. w

reductions in total and LDL -choIesterol and increaplasma apolipoprotein A-1 and B levels. Normal

tion of lipid levels occurred in a substantial num

of subjects with continued supplementation for

year.^""^^ L-camitine supplementation (2 g daily)

deereased triglycerides in individuals with essen

hypertension.*'

In a study of pediatrie patients on dialy

oral L-carnitine at 50 mg/kg/day for 30 days resu

in significant decrease in apolipoprotein B lev

with no changes in other lipid parameters.^'

L-eamitine (2 g daily) significantly redulipoprotein(a) (Lp(a)) levels in 14 of 18 subje

Reductions inLp(a) were greater in individuals w

more marked elevations prior to supplementat

in a significant number of subjeets the reduc

of Lp(a) resulted in a return to thenormal rang

Similar results were found in hypercholesterole

patients newly diagnosed with type 2 diabetes, w

significant deereases in Lp(a) levels noted after t

and six months of 1 g L-carnitine twice daily. O

measurements taken but not significantly impa

by L-carnitine were body mass index, fasting g

cose, postprandial glucose, glycosylated hemoglo

LDL- and HDL-cholesterol. total cholesterol, trig

erides, and apolipoproteins A-1 and B / '

Diabetes/Insulin ResistanceHealthy volunteers and type 2 diabetics

ceived an infusion of L-carnitine or saline,

which plasma glueose and insulin levels were

lyzed. Insulin-mediated glueose uptake was sig

cantly higher in both groups receiving L-earncompared to the saline groups, indicating impro

insulin sensitivity from carnitine.^

A small study found 500-mg intramusc

injections ofL-carn itine twice daily for 15 days re

ed in improvement in painful diabetic neuropathy.

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onograph L-Carnitine

In a small study. 15/18 cancer patients pre-

a significant cause of fatigue in this popu-

at 250 mg/day, increasing in

of 500 mg. to a maximum dose of 3 g

of supplementation, patients

in fatigue, de-

nic Fatigue SyndromeThirty-five patients with chronic fatigue syn-

tohave low free carnitine.

carnitine, and acylcarnitine c ompa red to controls,

a statistically significant correlation between to-

or amantadine (a drug that

in patients with multiple

a two-week washout period. Half of the

of the study, mainly due to in-

of the amantadine. However, the carnitine

upplem entation resulted in only one dropout and im-of 18 parameters studied.^'

Fatty LiverL-carnitine ame liorates ethanol-induced fatty

liver in animals;""* how ever, it has not been investi-

ated in humans for this condition.

HepatitisA study found plasma carnitine levels were

significantly lower in children with chronic hepatitis

B than in healthy controls. In addition, carnitine lev-

ls corresponded inversely to extent of liver fibrosis

and inflammation/'*

In a single case report, a patient with hyper-

ammonemia associated with a combination of hepati-

tis C, dialysis, and low free carniline levels responded

to IV L-earnitine. Within three hours of a single 2-g

dose, the patient progressed from comatose to normal

mental status.^'

Hepatic Encephalopathy from CirrhosisL-carnitine (2 g twice daily) orplacebt) was

administered to 120 patients with hepatic encepha

lopathy for 6(J days. Fasting scrum ammonia levelswere significantly lower at 30 and 60 days compared

to baseline and placebo. Mental function was also

significantly improved by L-carnitine. as measured

by NCT-A. an accepted psychometric test for menta

status in cirrhotic patients. The researchers speculate

L-carnitine decreases brain and blood ammonia lev

els by stimulating urcagenesis.**'

HIV and ImmunityDaily infusions of L-carnitine (6 g) for fou

months resulted in an increase in CD4 cou nts in HIV

positive subjects who were not taking anti-retro vira

therapy."

Administration of L-carnitine (6 g daily for

two weeks) to AIDS patients treated with zidovudine

(AZT) resulted in improved immunity and a reduc

tion in scrum levels of tumor necrosis factor-alpha.^

In another study on HIV patients on AZT and

didanosine (DDl). a subgroup was assigned to also

receive 6 g L-carnitine daily. Addition of carnitine

greatly reduced the negative effects of the drugs, including apoptosis of CD4 and CD8 cells and oxida

tive stress. No toxicity or decrease in drug effective

ness was noted.^•'

HyperthyroidismL-camitine is believed to be aperipheral an

tagonist of thyroid hormone activity in some tissues

A randomized, double-blind, placebti-controlled. six

month trial reported both 2- and 4-g daily doses o

L-carnitine prevented and reversed hyperthyroidism

related symptoms, including exerting a beneficial effect on bone mineralization.^'

Male InfertilityOral administration of L-carnitinc (3 g daily

for four months) resulted in significant improvement

in sperm number, quality, and motility in patients with

inadequate sperm.'•'''^^ In another double-blind, cross

over trial, 100 infertile males were supplemented

with 2 gL-carnitine daily or placebo for two months

followed by a two-month washout period, and finally

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L-Carnitine Monogra

two months on theopposite treatment. Statistically

signilicant im provem ents in sperm count and motility

were observed in the L-carnitine group.'" The same

researchers conducted a second study on 56 infertilemales and found the combination of L-carnitine (2 g

daily) and acetyl-L-carnitine (1 g daily) led to signifi-

cant improvement in sperm motility.'^''

Renal Failure!DialysisL-caniitine has been e.xtensively studied for

patients in renal failure. Su pplem entation, either oral-

ly or intravenously, mitigates some of the disorders

associated with dialysis, including renal anemia, car-

diac dysfunction, insulin resistance, lipid abnormali-

ties, and oxidative stress.*'*"''

Treatment for eight months with 1 g L-car-

nitine three times weekly, administered IV during di-

alysis sessions, resulted in improved left ventricular

ejection fraction.'"^

The National Kidney Foundation - Kidney

Disease Outcome Quality Initiative recommends the

use of L-carnitine for the treatment of anemia associ-

ated with chronic renal failure/'^

Respiratory Distress in PrematureInfants

A combination of L-carnitine (4 g daily for

five days) and betamethasone given to women in the

prenatal period reduced both the incidence of respira-

tory distress syndrom e and the mortality of pretnature

newborns.''''

L-carnitine supplementation to preterm in-

fants at a dose of 30 mg/kg/day in one study''^ and

15 mg/kg/day in a second study"^ did not result in

significant differences between supplementation and

placebo groups in frequency of apnea. weight gain.

or length of hospital stays. From the above studies,

it appears prenatal supplementation may be of more

benefit than newborn supplementation.

A case of siblings presenting with apnea and

periodic breathing, along with biochemical defects

consistent with a non-specific abnormality of beta-

oxidation, suggests L-carnitine might prevent some

cases of sudden infant death syndrome.""

Weight LossIn a double-blind study, investigators fo

no effect of L-carnitine supplementation on wei

loss or any va riable of body com position measure

Nutrient-Nutrient InteractionsA deficiency of ascorbic acid may decre

endogenous biosynthesis of carnitine."^- In gui

pigs, supplementing the diet with ascorbic acid

creased carnitine biosynthesis."

A case report describes normalization of

nitine levels following administration with ribo

vin.''^ In rats, administration of vitamin B12 increa

carnitine biosy nthesis." Choline supplementation

pears to decrease carnitine synthesis.^''

Drug-Nutrient InteractionsAnticonvulsant medications, including p

nobarbital. valproic acid, phenytoin. and carbam

pine. have a significant lowering effect on cami

levels."

The antibiotic pivampicillin negatively

pacts carnitine metabolism.""^

L-carnitine should be used cautiously, i

all. with pentyienetetrazote. since evidence suggthe combination might exacerbate the side effect

the drug.^^

Evidence suggests supplemental L-carni

might prevent cardiac complications secondary to

terleukin-2 immunotherapy in cancer patients'"'

cardiac toxicity secondary to adriamycin.**'

L-carnitine. when used concurrently w

AZT. appears to prevent thedrug-induced dest

tion of myotubcs, preserve the structure and vol

of mitochondria, and prevent the accumulation of

ids.'^-L-carnitine supplementation helps pre

elevation in liver enzymes, as well as the mya

weakness, and hypotension induced by isotretinoi

Emetine (ipecac) appears to promote ca

tine deficiency.*" A case report suggests carnitine

ficiency was induced in a patient receiving sulfa

zine and pyrimethamine."^

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Monograph L-Carnitine

Evidence also suggests L-carnitine potenti-

ates the anti-arrhythmic effect of propafenone and

mexiletine in patients with ischemia/'*

Side Effects and ToxicityA variety ofmild gastrointestinal symptoms

have been reported, including transient nauseaand

vomiting, abdominal cramps, and diarrhea.

The LD,,, inmice is 19.2 g/kg. Mutagenicity

data indicate no mutagenicity; however, experiments

to determine long-term carcinogenic ity have not been

conducted.

DosageThe average therapeutic dose is I -2g twoto

three times daily for a total of2-6 gdaily. No advan-

tage appears toexist ingiving anoral dose greater

than 2g atone time, since absorption studies indicate

saturation at this dose.

Warnings and ContraindicationsL-carniiine is listed as pregnancy category

, indicating animal studies have revealed no harm

o the fetus but that no adequate studies inpregnant

women have been conducted. L-carnitine has beeniven to pregnant women late inpregnancy with

esulting positive outcomes.

The racemic mixture (D.L-carnitine) should

e avoided. D-carnitine is not biologically active

nd might interfere with the proper utilization of

somer. Inuremic patients, use ofthe racemic

ixture has been correlated with myasthenia-like

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L-Carnitine Monogra

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Monograph L-Carnitine

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57.

58 .

59 .

60.

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62.

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64.

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66.

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