ISSN 1519-6984 (Print)

ISSN 1678-4375 (Online)

THE INTERNATIONAL JOURNAL ON NEOTROPICAL BIOLOGY

THE INTERNATIONAL JOURNAL ON GLOBAL BIODIVERSITY AND ENVIRONMENT

Review Article

Biomedical role of L-carnitine in several organ systems, cellular

tissues, and COVID-19
Papel biomédico da L-carnitina em vários sistemas de órgãos, tecidos celulares e
COVID-19

I. S. Al-Dhuayana* 
Imam Abdulrahman Bin Faisal University, College of Science, Department of Biology, Dammam, Saudi Arabia.
a

Abstract
Carnitine is a conditionally necessary vitamin that aids in energy creation and fatty acid metabolism. Its bioavailability
is higher in vegetarians than in meat-eaters. Deficits in carnitine transporters occur because of genetic mutations
or in conjunction with other illnesses. Carnitine shortage can arise in health issues and diseases—including
hypoglycaemia, heart disease, starvation, cirrhosis, and ageing—because of abnormalities in carnitine control.
The physiologically active form of L-carnitine supports immunological function in diabetic patients. Carnitine
has been demonstrated to be effective in the treatment of Alzheimer’s disease, several painful neuropathies, and
other conditions. It has been used as a dietary supplement for the treatment of heart disease, and it also aids in
the treatment of obesity and reduces blood glucose levels. Therefore, L-carnitine shows the potential to eliminate
the influences of fatigue in COVID-19, and its consumption is recommended in future clinical trials to estimate its
efficacy and safety. This review focused on carnitine and its effect on tissues, covering the biosynthesis, metabolism,
bioavailability, biological actions, and its effects on various body systems and COVID-19.
Keywords: L-carnitine, diabetes mellitus, cardiovascular disease, obesity.

Resumo
A carnitina é uma vitamina condicionalmente necessária que auxilia na geração de energia e no metabolismo de
ácidos graxos. Sua biodisponibilidade é maior em vegetarianos do que em carnívoros. Déficits nos transportadores
de carnitina ocorrem devido a mutações genéticas ou em conjunto com outras doenças. A escassez de carnitina
pode surgir em problemas de saúde e doenças – incluindo hipoglicemia, doenças cardíacas, fome, cirrose e
envelhecimento – devido a anormalidades no controle da carnitina. A forma fisiologicamente ativa da L-carnitina
suporta a função imunológica em pacientes diabéticos. A carnitina demonstrou ser eficaz no tratamento da doença
de Alzheimer, várias neuropatias dolorosas e outras condições. Tem sido utilizado como suplemento dietético para
o tratamento de doenças cardíacas, também auxilia no tratamento da obesidade e reduz os níveis de glicose no
sangue. Portanto, a L-carnitina mostra potencial para eliminar as influências da fadiga na COVID-19 e seu consumo
é recomendado em futuros ensaios clínicos para estimar sua eficácia e segurança. Esta revisão enfocou a carnitina
e seu efeito nos tecidos, abrangendo a biossíntese, metabolismo, biodisponibilidade, ações biológicas e seus efeitos
em vários sistemas corporais e COVID-19.
Palavras-chave: L-carnitina, diabetes mellitus, doença cardiovascular, obesidade.

1. Introduction

L-Carnitine (LC) is a quaternary ammonium compound. an individual’s demand for LC may make it an essential
It is considered and its two derivatives (acetyl-L-carnitine vitamin (Seim et al., 2001; De Grandis and Minardi, 2002).
and propionyl-L-carnitine) essential amino acid lysine The carnitine molecule has a gamma trimethyl amino
which plays important role in cellular energy metabolism, beta-hydroxybutyric acid structure with D and L forms;
as shown in Figure 1. In 1905, it was discovered in beef D-carnitine inhibits LC’s function. Only the L-form, which
(‘carnus’ in Latin). Carnitine’s L-isomer is the only isomer is biologically active, is generated endogenously in tissues
that is physiologically active (Rebouche, 2006). LC, which (such as the brain, kidneys, and liver) through conversion
resembles a vitamin in mealworms, was given the moniker from amino acids, including lysine and methionine; this
vitamin BT. Humans and other higher animals can generate process accounts for 25% of the body’s LC. The remaining
LC; thus, vitamin BT is a misnomer. However, in rare cases, 75% is derived from food sources (Çitil, 2002; Hoppel, 2003).

*e-mail: ialdhuayan@[Link]
Received: September 7, 2022 – Accepted: November 20, 2022
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

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Al-Dhuayan, I.S.

Figure 1. L-Carnitine chemical structures and its two derivatives (Durazzo et al., 2020).

It is typically consumed in food and stored in the skeletal that convert fatty acids into acetyl-CoA. In the cytoplasm,
muscle (Rebouche, 2004). The fundamental function of fatty acids are converted to acyl-CoA, and LC stimulates
this key metabolite is to ensure the movement of fatty the transfer of an acyl group from the cytoplasm to
acids from the cytoplasm through the mitochondria so the mitochondria by binding to the carnitine shuttling
that they can be used for mitochondrial oxidation (Seline system on the mitochondrial membrane. L-Carnitine
and Johein, 2007). LC assists in the beta-oxidation of palmitoyltransferase-1 (CPT I), which is located on the
fatty acids, which serve as energy sources in the form of outer surface of the mitochondria, releases CoA to form
acylcarnitine. Second, it protects mitochondria from the an acylcarnitine. Acylcarnitine is transported across the
damaging effects of free coenzyme A (CoA) generated mitochondrial membrane and into the mitochondria matrix
during the digestion of short- and medium-chain fatty via L-carnitine/acyl-L-carnitine translocase (CAC), as shown
acids (Calabrese et al., 2012). in Figure 2. In the mitochondrial matrix, the acyl group of
LC has been shown to improve physical performance in carnitine is dissociated and linked back to coenzyme A by
patients with certain illnesses, including advanced cancer LC palmitoyltransferase-2 (CPT II), which is present in the
(Bloomer et al., 2013), fatigue (Gramignano et al., 2006), inner mitochondrial membrane, to import long-chain FA
metabolic syndrome, and cardiovascular disease (CVD) into the mitochondria for beta-oxidation, which provides
(Delaney et al., 2013). energy for cells (Wang et al., 2021b).
Long-term supplementation with LC is likely safe at Carnitine homeostasis is maintained in healthy
doses of 2 g/day, but it may lead to indigestion, vomiting, persons by dietary carnitine absorption, renal carnitine
diarrhoea, nausea, or fishy body odour at doses of 3 g/day reabsorption, and endogenous LC production. Cell
(Rebouche, 1999). membrane transporters distribute carnitine between the
extracellular compartment and the tissues, maintaining
the concentration gradient between them. Humans can
2. Metabolism, Bioavailability, and Biosynthesis obtain carnitine from red meat, chicken, some types of
fish, and dairy products; thus, the intake of carnitine for
Cellular metabolism is a complex biochemical process vegetarians is very low because their diets lack foods rich
that is necessary for organisms to maintain life. It mainly in carnitine sources. The daily dietary intake of carnitine
occurs in the mitochondria, which work to convert should range between 1 and 15 μmol/kg of body weight.
food into energy by oxidising fatty acids. Therefore, a Carnitine from food is absorbed by the epithelial cells
disruption in mitochondrial function leads to deficient lining the small intestine, where it is transported by simple
energy production, an accumulation of fatty acids in the diffusion into the blood circulation. The kidneys reabsorb
cell, and an increase in reactive oxygen species (Virmani carnitine through active transport by transporters present
and Cirulli, 2022). LC is an essential component and plays in the brush border membranes of the renal tubular cells,
a role in mitochondrial processes, ATP energy production, and when the dietary intake of carnitine decreases, its
and fatty acid metabolism. It is also involved in controlling reabsorption by the kidneys increases (Rebouche, 2004;
gluconeogenesis, ketogenesis, cellular detoxification, and Kraemer et al., 2008).
stabilising cell membranes (Wang et al., 2021 a). In the The amino acids lysine and methionine can be converted
mitochondria, the transport of long-chain fatty acids for to LC in humans via a multi-step process involving
energy production in peripheral tissues is dependent on LC numerous cells. Lysine methyltransferases, which are
(Center et al., 2000). LC is necessary for the oxidation and utilised as methyl donors, are made from the amino
transport of fatty acids through the inner mitochondrial acid methionine and methylate protein-bound lysine
membrane (Broad et al., 2011; Pandareesh and Anand, 2013). to generate 6-N-trimethyl lysine, which is essential for
Carnitine is necessary for the esterification of long carnitine synthesis. The hydroxylation of 6-N-trimethyl
fatty acid chains in the mitochondria, which provides lysine yields 3-hydroxy-6-N-trimethyl lysine, which
energy through beta-oxidation via a series of reactions is separated into 4-trimethylaminobutyraldehyde and

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Figure 2. The role of L-carnitine in fatty acid metabolism in mitochondria (Wang et al., 2021b).

Figure 3. L-Carnitine biosynthesis takes place in six steps, interspersed with four important enzymes (green box) (Furusawa et al., 2008).

glycine; subsequently, trimethylaminobutyraldehyde is system. It also aids in the appropriate use of glucose
dehydrogenated to form 4-N-trimethylaminobutyrate by the cell, improving glucose metabolism in patients
(γ-butyrobetaine), and this compound produces LC with diabetes and reducing problems such as tiredness,
(3-hyroxy-4-N-trimethylaminobutyric acid or β-hydroxy-γ- sleeplessness, and mental activity (Karalis et al., 2020).
N-trimethylaminobutyric acid). Endogenous LC production Clinical supplementary LC might help people with
is mediated by four enzymes, as shown in Figure 3. Except poor glucose metabolism improve their glucose tolerance.
for butyrobetaine hydroxylase, which is not found in the LC increases the oxidation of fatty acids, which can
cardiac or skeletal muscle, all four enzymes are widely contribute to insulin resistance in the skeletal muscle;
distributed. However, these enzymes are abundant in therefore, it may be advantageous to these patients
the liver, testes, and kidneys in humans (Rebouche, 2014). (Ringseis et al., 2013). Supplemental LC was found to
L-Carnitine is produced in the liver and transported to lower insulin resistance compared with placebo in
the cardiac and skeletal muscle, where it is required for fatty a meta-analysis including patients with weakened
acid oxidation, but it cannot be produced in vegetarians; it fasting glucose, type 2 diabetes (T2D), and non-alcoholic
was synthesised at a rate of 1.2 mol/kg of body weight/day steatohepatitis (Xu et al., 2017). A meta-analysis of four
(i.e., persons who receive relatively little dietary carnitine) randomised, placebo-controlled studies demonstrated
(Evans and Fornasini, 2003). The quantity of methylation on a decrease in fasting plasma glucose concentration but
peptide-linked lysine and the average protein rotation controls no change in glycated haemoglobin concentration in
the pace of LC production. Increased lysine in the diet can patients with T2D mellitus treated with acetyl-L-carnitine
boost endogenous LC synthesis; by contrast, LC intake does (ALCAR) (Vidal-Casariego et al., 2013). Supplementing
not affect the rate of endogenous synthesis (Rebouche, 2014). with (acyl)-L-carnitine may lower fasting blood glucose
and glycated haemoglobin concentrations but not insulin
resistance (Asadi et al., 2020). The impact of ALCAR was
3. Biological Activities studied in 229 patients with diabetes, hypertension, and
dyslipidaemia in a randomised, controlled experiment.
3.1. L-Carnitine and diabetes mellitus The results showed that supplementing with ALCAR
LC is an essential component of the human body that (1 g/day for 6 months) had no influence on blood
promotes the proper function of the heart and muscular pressure, markers of glucose homeostasis, or blood

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Al-Dhuayan, I.S.

lipid profile (Parvanova et al., 2018). However, therapy stores (Flanagan et al., 2010). LC supplementation for
with LC has proven to be beneficial for the control of 12 months in patients with chronic heart disease patients
diabetes, insulin resistance, high blood pressure, and was demonstrated to reduce chronic heart diseases and
dyslipidaemia in prior investigations (Zhang et al., 2014). mortality. As an oral treatment, it was demonstrated to
In patients with T2D, LC supplementation resulted in a minimise myocardial damage while enhancing glucose
considerable reduction in lipid profile levels. According metabolism and reducing the toxicity of elevated free
to the National Cholesterol Education Program (NCEP, fatty acid levels (Xue et al., 2007).
2001), all risk factors for diabetic patients should be Several studies have found that administering LC right
decreased to lower patients’ total CVD risk. after a heart attack might help to decrease ischemia-
About half of people with diabetes mellitus have induced cardiac muscle damage. Taking oral LC in addition
peripheral nerve dysfunction, and about a third of those to normal pharmacological therapy for a year decreased
with diabetes have persistent neuropathic pain (Tesfaye mortality and angina episodes considerably (Davini et al.,
and Selvarajah, 2012). As diabetic peripheral neuropathy 1992). Another controlled study including 96 patients found
progresses, it can cause recurring foot sores and infections, that intravenous LC treatment reduced levels of creatine
which can require amputation (Dy et al., 2017). kinase-MB and troponin-I, two markers of myocardial
Rolim et al. (2019) and Sima et al. (2005) identified injury, after myocardial infarction (MI) (Xue et al., 2007).
some studies that examined the effects of oral ALCAR However, not all clinical research has indicated that
supplementation in diabetic patients. ALCAR was shown supplementing with LC after a heart attack is beneficial.
to decrease the degree of pain and improve clinical In a randomised trial involving 60 people who had an acute
symptoms in patients with diabetic peripheral neuropathy, MI, no differences in heart function were found between
as evaluated by a visual analogue scale, according to low- those who received intravenous LC and those who received
quality data (Li et al., 2016). a placebo (Iyer et al., 1999). Another randomised study
found that LC therapy did not affect the incidence of heart
3.2. L-Carnitine and cardiovascular disease failure or death 6 months after MI (Tarantini et al., 2006).
In individuals who had acute MI, LC treatment reduced
LC functions as a vitamin in the body’s metabolic
the risk of death, ventricular arrhythmias, and angina.
activities. In a range of illnesses, including CVD, diabetes,
The rupture of an atherosclerotic plaque in a coronary artery
and dyslipidaemia, high levels of LC have been shown to obstructs the blood flow to the heart muscle, causing injury
be beneficial (Ferrari et al., 2004). or damage to the heart muscle and MI (DiNicolantonio et al.,
Because it is unable to produce carnitine, human 2013). Because oral LC supplements are unlikely to be
skeletal and cardiac muscle absorbs relatively high levels absorbed, procedures that mix intravenous and oral
of it from the plasma. In carnitine-acylcarnitine carrier administration are equal to those that employ only oral
(CAC) deficiency, the heart is one of the most damaged administration (Evans and Fornasini, 2003).
organs; CAC promotes the import of fatty acyl moieties into Oral LC supplementation for a long time has been
the mitochondria, where they are oxidised via the beta- shown to decrease metabolic syndrome and CVD risk
oxidation pathway by increasing carnitine/acylcarnitine factors (Wong et al., 2016). According to Wu (2016), LC
exchange. The heart obtains most of its energy from this can improve lipid profiles and reduce diabetes and heart
source, so CAC deficiency causes cardiomyopathy, cardiac disease while also improving clinical symptoms in patients
arrhythmia, cardiac insufficiency, and respiratory distress with diabetes and heart failure.
(Palmieri, 2008). Heart failure has also been linked to a When cardiomyocytes experience cardiac failure, they
lack of carnitine (Cave et al., 2008). have problems converting substrates into energy; LC levels
The mechanism or mechanisms behind LC’s actions in in the blood are reduced after coronary artery graft surgery,
cardiovascular disorders remain unknown. The effects of and oxidative stress is increased. LC supplementation in
long-term LC administration on the inflammatory process these individuals has shown benefits in the clinical setting
associated with arterial hypertension were identified in (Silva et al., 2017).
a rat model (Miguel-Carrasco et al., 2008). Wang et al. (2018) mentioned that LC is an endogenous
LC, the physiologically active dietary carnitine cofactor and may be associated with an increase in
(3-hydroxy-4-N-trimethylaminobutyric acid), is a mitochondrial oxidation and production of cardiac energy.
promising alternative medication for secondary heart It increases fatty acid transport across the mitochondrial
disease prevention. The carnitine/organic cation matrix, lowering oxidative stress, inflammation, and
transporter-2 (OCTN2) allows cardiac muscle cells to myocyte necrosis while also offering cardioprotective
receive LC from outside sources. OCTN acts as a carnitine benefits. LC also adjusts calcium influx, intracellular enzyme
transporter in the heart, kidney, liver, pancreas, intestine, release, and membrane phospholipid content, all of which
brain, placenta, trachea, lung, and thyroid. The carnitine- contribute to cellular homeostasis. As a result, dietary and
acylcarnitine carrier (CAC) is a protein that allows cardiac intravenous exogenous carnitine supplementation are
mitochondria to oxidize fatty acyl, which is the main source efficient strategies for reducing ventricular dysfunction,
of energy for the heart muscle, and deficits in LC or its ischemia-reperfusion damage, cardiac arrhythmia, and toxic
transporter CAC can cause heart disease (Flanagan et al., myocardial injury are all reduced, all of which are prevalent
2010). symptoms of CVD. Hypertension, hyperlipidemia, diabetic
LC supplementation can benefit patients with heart ketoacidosis, hyperglycemia, hyperglycaemia insulin-
disease because it assists in the return of cardiac energy dependent diabetes mellitus, insulin resistance, obesity,

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and other variables are all improved by LC. Individuals over 1500 mg/day (Asadi et al., 2020). The meta-analysis
with acute and chronic heart failure in various age groups, also showed a decrease in the level of total cholesterol
including infants, juveniles, young adults, adults, and older and TAG in the blood of patients with chronic hepatitis C
adults, can benefit from LC. who took LC supplements at a dose of 2000 mg/day for
approximately 24 weeks, and no changes in the levels of
3.3. L-Carnitine and lipid profile HDL or LDL were observed (Abbasnezhad et al., 2020).
LC boosts fat oxidation and glycogen sparing during
exercise, which increases physical performance (Johri et al., 3.4. L-Carnitine and weight loss
2014). It has a variety of physiological functions, including Obesity is a worldwide epidemic that can lead to
antioxidant preservation and increased nitric oxide dyslipidaemia (Fried et al., 2008), diabetes (Pagotto et al.,
synthesis (Bacurau et al., 2003). Moreover, LC improves 2008), fatty liver (Marović, 2008), and heart problems
energy generation from fatty acid oxidation (Gulcin, 2006), (Artham et al., 2008). Individuals often use pharmacotherapy
particularly from adipose tissue triglycerides (TAG), and to help them lose weight. Carnitine is one of the medications
optimises the utilisation of adenosine triphosphate (ATP) that claim to help people with weight loss.
as a fuel substrate during exercise (Sahlin et al., 2008). Obesity is a severe health issue that has become
LC also regulates the mitochondrial ratio and activates increasingly linked to elevated rates of mortality and
carnitine acyltransferases (CAT), which transport fatty morbidity throughout the world. Weight reduction is
acids across the mitochondrial membrane (Karlic and becoming more popular as weight control becomes
Lohninger, 2004). increasingly challenging in the modern environment.
Carnitine may influence triglycerides as well as total Anti-obesity medicines do not have the same negative
cholesterol and its fractions. In obese and insulin-resistant side effects as invasive operations, and thus they are
ponies, 14 weeks of carnitine administration reduced blood more popular than alternative choices, such as physical
lipid profile levels (Schmengler et al., 2013). Furthermore, activity. Carnitine has been used to treat heart disease
Coleman and Lee (2004) suggested that with elevated (Shang et al., 2014), end-stage renal disease (Chen et al.,
physiological carnitine levels in the liver, very-low-density 2014), dialysis-related hypertension (Lynch et al., 2008),
lipoprotein (LDL), triglyceride, and cholesterol secretion persistent depressive disorder, and fatty liver disease
rates were lower. As a result, reduced LDL production (Kriston et al., 2014). However, the data on carnitine’s
is predicted to raise plasma high-density lipoprotein anti-obesity properties are currently equivocal. In one
(HDL) levels. Athletes have long been interested in using study, weight reduction was assessed using two variables:
carnitine to improve physical performance by enhancing the individual’s weight and their body mass index (BMI).
ATP production, with several types of carnitine being Only seven participants had suitable data for quantitative
employed. Previous research suggested that muscle examination. This study had good methodological quality,
carnitine is reallocated in the muscle after intense physical demonstrated that LC had a positive influence on weight
exercise (Muller et al., 2002). and BMI, and showed that LC could help people with
LC is an unbound, water-soluble amine, allowing chronic illnesses, including diabetes and obesity, lose
for an increase in fatty acid metabolism (Hoppel, weight (Pooyandjoo et al., 2016).
2003). Furthermore, LC may alter glucose catabolism LC, which is important for lipid catabolism and energy
by transporting acetate from the mitochondria to the generation, is also important for muscle fuel metabolism
cytoplasm, lowering the acetyl CoA/CoA ratio in the during exercise and regulating muscle fuel metabolism
mitochondria and enhancing pyruvate dehydrogenase (Kim et al., 2015). Along with the body’s requirement
activity. Other studies have found that LC may raise fasting for LC during high-intensity exercise, this suggests that
TAG in patients with diabetes (Rahbar et al., 2005). LC ingestion enhances fat oxidation during extended
Therefore, pharmaceutical agents that can correct exercise, preserves glycogen stores, and delays tiredness
blood lipid abnormalities, particularly in people with T2D, onset (Kraemer et al., 2008).
are critical. Accordingly, the impact of nutraceuticals on With its two impacts on glucose and lipid metabolism,
cardiovascular risk factors is a currently a hot research LC may aid metabolic illnesses such as T2D and
topic (Ward et al., 2017). The pharmacological benefits of hypertriglyceridemia. LC is a well-known weight-loss and
LC as an additional treatment for dyslipidaemia, notably fat-burning substance, and according to a meta-analysis,
in individuals with T2D, have been described in several supplementing with LC lowered body weight, BMI, and
investigations (Rahbar et al., 2005). fat mass (Pooyandjoo et al., 2016; Talenezhad et al.,
LC is a vitamin-like molecule made up of lysine and 2020). Supplementing with LC lowers blood pressure by
methionine that is necessary for the fatty acid oxidation minimising interactions with the nitric oxide system and
in the mitochondria and the protection of cell membranes insulin resistance (Rajasekar et al., 2007).
from free radical damage (Peivandi et al., 2010). In patients According to Askarpour et al. (2019), LC supplementation
with chronic renal disease, intake of LC supplements led to at taken 2 g/day lowers diastolic blood pressure
a decrease in the level of cholesterol and triglycerides, and (DBP) without changing systolic blood pressure (SBP).
an increase in haemoglobin and HDL (Naini et al., 2012). By enhancing carbohydrate oxidation and lowering fatty
In a meta-analysis of patients with cardiovascular risk acid oxidation, LC supplementation at a dose of 2-3 g/day
aiming to evaluate the effect of LC intake on lipid profile, was linked to improved fasting blood sugar (FBS) and insulin
lipid level improvement was demonstrated at doses of resistance (Vidal-Casariego et al., 2013). LC plays a key role

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Al-Dhuayan, I.S.

in fatty acid beta-oxidation and lowers the availability a lack of evidence, LC has been recommended as a feasible
of free fatty acids for triglyceride production. In a study treatment for restoring mitochondrial function, minimising
conducted by Malaguarnera et al. (2009), LC lowered TAG toxic metabolite formation, and counteracting or reversing
concentrations while increasing HDLc concentrations. the toxic effects of valproic acid. A comprehensive analysis
The intake of LC in patients who are obese and identified only eight occurrences of acute valproic acid
overweight leads to a decrease in body weight and exposure in adults and children, as well as one study that
BMI, suggesting that it has an anti-obesity effect published safety data from 674 people. Because LC has low
(Askarpour et al., 2020). oral bioavailability, intravenous therapy was recommended;
in addition, most overdose patients were given activated
3.5. L-Carnitine and liver and kidney disease charcoal, rendering oral LC ineffective. According to data
The most prevalent dose-limiting adverse effects of from these cases and toxicological sources, the most
cisplatin-induced chemotherapy are hepatic and renal common loading dose was 100 mg/kg, with another dose of
damage (Neamatallah et al., 2018). Using LC to reduce the 50 mg/kg, to address ongoing or delayed toxicity induced by
possible negative effects of cisplatin is beneficial during valproic acid absorption. Despite the dearth of data and the
chemotherapy. Elevated liver enzyme activity is recognised likelihood of publication bias, the authors concluded that
as an indication of cellular infiltration and loss of function LC treatment was appropriate for individuals with acute
of hepatocytes because these enzymes are discharged overdose and low levels of consciousness (Perrott et al.,
into the blood when the hepatocyte plasma membrane 2010). In addition, a case report described the use of LC
is disrupted (Jia et al., 2018; Farid et al., 2021; Fadl et al., to treat PEG-asparaginase-induced hepatotoxicity in a
patient with acute lymphoblastic leukaemia (Alshiekh-
2020). It was shown that cisplatin-induced hepatotoxicity
Nasany and Douer, 2016).
was accompanied by a considerable change in blood
Yang et al. (2014) conducted a systematic review and
liver enzymes. Cisplatin is absorbed by and deposited
meta-analysis to assess prior findings showing that LC
in the liver cells, producing damage and an elevation
had favourable effects on haemoglobin and erythropoietin
in liver enzyme activity (Mohamed and Badawy, 2019).
dosage in patients undergoing maintenance haemodialysis.
Furthermore, cisplatin raises creatinine and urea levels
Although LC supplementation reduced LDL cholesterol
(Sadeghi et al., 2020) and indicates cisplatin-induced
and C-reactive protein (CRP), it had no effect on other
nephrotoxicity. By contrast, Cayir et al. (2009) ascribed
lipid markers, haemoglobin, haematocrit, albumin, or the
cisplatin hepatotoxicity and nephrotoxicity to free radical
erythropoietin dosage required. The drop in LDL cholesterol
formation in kidney and liver cellular, which causes
was assumed to be insignificant in clinical terms. There
cellular damage.
were no known negative consequences (Chen et al., 2014).
Furthermore, LC is a naturally occurring substance
Because of a lack of evidence, the Renal Illness Improving
that is required to generate ATP (Tunez et al., 2007).
Global Outcomes (KDIGO) clinical practice guidelines for
As a result, it contains antioxidant qualities and protects
anaemia in chronic renal disease do not advocate LC as an
numerous tissues from oxidative stress (Cayir et al., 2009).
adjuvant treatment (KDIGO, 2012).
In a rat model, LC lowered liver enzyme activity, oxidative
stress, and thioacetamide and tilmicosin-induced damage
(Aboubakr et al., 2020). In rats with acute renal failure,
LC increased the antioxidant enzyme activity in kidney 4. Physical Health
tissues (Aydogdu et al., 2006). Therefore, LC’s ability to
protect numerous tissues may be due to its antioxidant 4.1. Physical performance
effect, resulting in membrane permeability protection The importance of LC’s function in energy metabolism
(Augustyniak and Skrzydlewska, 2009). LC protects has sparked interest in its potential to boost athletic
against mitochondrial toxic chemicals and oxidative stress performance. LC supplementation can be used for acute
(Barhwal et al., 2007). It also enables beta-oxidation, (2-4 g/day taken one hour before an exercise session) or
which reduces the detrimental effects of free fatty acids in the short-term (for 2 to 3 weeks). According to several
(Furuno et al., 2001). small studies, it can help with energy generation, cardio-
People with acute or chronic liver illness can exhibit respiratory fitness, and endurance capacity during physical
hepatic encephalopathy, which refers to a variety of activity (Fielding et al., 2018).
neuropsychiatric signs and symptoms. There may be no Because of its function in converting fat into energy,
indications of subclinical hepatic encephalopathy other LC is a popular substance among athletes as a potential
than aberrant conduct on psychometric tests or vague ergogenic aid (Kim et al., 2015). Propionyl-L-Carnitine
symptoms. Disorientation, evident personality changes, (1 g/day or 3 g/day) did not increase aerobic or anaerobic
inappropriate conduct, somnolence, stupor, confusion, exercise performance in 32 healthy people in an 8-week
and coma are among the symptoms of overt hepatic study (Smith et al., 2008). In a study examining the effects
encephalopathy. The liver’s failure to metabolise neurotoxic of LC supplementation on plasma and skeletal muscle
chemicals, such as ammonia, is assumed to be the source carnitine concentrations and physical performance in
of mental changes (Wijdicks, 2016). 16 vegetarian and 8 omnivorous male volunteers, the
Although excess valproic acid does not cause toxidrome, plasma carnitine levels in vegetarians were 10% lower at
it can deplete hepatic LC reserves, making mitochondrial baseline than those of omnivores. However, the carnitine
transport via the carnitine shuttle more difficult. Despite levels in skeletal muscle phosphocreatine, ATP, glycogen,

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and lactate were equal in vegetarians and omnivores, as the muscles. In a retrospective analysis of patients with
were the measures of physical performance after exercise. cirrhosis, those who received LC had lower rates of skeletal
Although LC treatment raised plasma carnitine levels in muscle loss for at least 6 months compared with those
vegetarians above the levels reported in omnivores, no who did not (Ohara et al., 2018).
differences in energy metabolism or physical performance
were observed between the two groups (Novakova et al., 4.4. Muscle cramps
2016). The skeletal muscle stores more than 95 per cent of Muscle cramps are painful involuntary skeletal
the body’s total carnitine and is involved in key metabolic muscle contractions. LC supplementation at levels of
processes, such as ATP synthesis (Stephens et al., 2007; 0.9 to 1.2 g/day for 8 weeks was found to be effective
Kim et al., 2015). in patients with cirrhosis in two uncontrolled studies
(Nakanishi et al., 2015; Hiraoka et al. 2019), which found
4.2. Frailty that LC supplementation was safe and could be used to
Frailty is a serious age-related health problem marked reduce cramp frequency. However, supplemental LC has
by a considerable decrease in physiological reserves and a not yet been proven to be effective in reducing muscular
greater sensitivity to shock. Its phenotype (from pre-frailty cramps in cirrhotic individuals. A study of 69 patients
to frailty) is a major predictor of severe unfavourable health with diabetes revealed that those who took LC once per
problems, such as cardiovascular illnesses (Veronese et al., day for four months had lower blood sugar levels, fewer
2017), depression (Feng et al., 2014), hospitalisation, loss muscle cramps, and a higher quality of life than those who
of fundamental daily activities, falls, fractures, and early took a placebo (Imbe et al., 2018). By contrast, there is
death (Vermeiren et al., 2016). Frailty is more frequent currently no evidence that supplementary LC can prevent
in older adults because of the steady decline in their muscular cramps in individuals receiving haemodialysis
functional ability and the increase in functional dependency (Lynch et al., 2008). To determine whether LC can assist
that occurs as people age (Siriwardhana et al., 2018). with cramping, researchers will need to conduct well-
Furthermore, being female, single marital status, a lack designed experiments.
of social support, a greater prevalence of comorbidities, Patients with ongoing symptoms of painful, involuntary
disability, and functional restriction have all been identified contractions of skeletal muscles at rest or waking them up
as important risk factors for the emergence of frailty at least three times in the previous month were included
(Manfredi et al., 2019). in a prospective uncontrolled, nonrandomised study
Frailty is a condition that affects older populations evaluating the effects of LC on reducing muscle cramps
and is marked by a deterioration in function and a loss of in patients with cirrhosis. Participants were given LC for
independence in performing everyday tasks. Unintentional 8 weeks and reported decreased cramping, and no negative
weight loss, fatigue, weakness, sluggishness, and physical consequences were observed (Nakanishi et al., 2015).
inactivity are indications of frailty (Fried et al., 2004). Early
stages of frailty are thought to be responsive to therapies
that might prevent negative outcomes, such as increased 5. L-Carnitine and Cellular Injury
hospitalisation and premature mortality (Vermeiren et al.,
The regulation of cell proliferation and differentiation
2016). One study investigated the theory that carnitine
is dependent on cellular metabolic activity, particularly
deficit leads to frailty by causing mitochondrial malfunction
mitochondrial metabolism. When applying engineering
(Crentsil, 2010). The results of study on 50 older adult
methods to drive tissue formation and repair, metabolism
showed that participants who received LC supplementation
may be a significant component to consider. Carnitine and
exhibited a lower frailty index score and improved strength
its derivative, acetylcarnitine, are tiny metabolites that
in a hand grip test, whereas those given a placebo did not
influence the activity of multiple mitochondrial metabolic
(Badrasawi et al., 2016).
pathways. Adult stem cells were employed as a platform
in both monolayer and 3D hydrogel culture systems to
4.3. Skeletal and muscle weakness investigate the impact of these two small compounds on
Skeletal and muscle mass loss is linked to a loss of mesenchymal tissue engineering. The authors examined
muscular strength and occurs as people age (Dhillon and the effects of these two small compounds on adult stem cell
Hasni, 2017) as well as in a variety of clinical diseases (Ebadi differentiation, as well as gene expression, cell proliferation,
and Montano-Loza, 2019). A low proportion of protein and extracellular matrix deposition. In both culture systems,
synthesis and degradation leads to skeletal muscle atrophy; the compounds inhibited adipogenesis while stimulating
according to a preclinical study, LC supplementation may osteogenesis and chondrogenesis. According to the findings
help increase this proportion (Ringseis et al., 2013). In a of our previous study, carnitine and acetylcarnitine may
randomised controlled experiment including 28 older impact the differentiation rate of adult stem cells by
women, LC supplementation had no impact on serum influencing mitochondrial metabolism. The action of
pro-inflammatory cytokine concentrations, body mass these two compounds suggests that such metabolites
and composition, or measures of skeletal muscle strength may be used in tissue-engineering systems to improve
(Sawicka et al., 2018). The presence of a defect in liver cell differentiation and tissue formation (Lu et al., 2015).
function in patients with cirrhosis led to weakness and The effects of LC (300 mg/kg/day) administered
loss of skeletal muscle mass; this study was the first to intraperitoneally to rats fed rations containing various
show the protective effect of LC supplementation on proportions of fish oil for 30 days on plasma LC, lipid

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Al-Dhuayan, I.S.

hydroperoxide (LPO), triglyceride, cholesterol, body weight, body weight, a decrease in biomarkers of oxidative stress
plasma-tissue antioxidant enzymes (superoxide dismutase, was observed (Fatouros et al., 2010).
carnitine acyltransferases), and glutathione levels were Administration of LC reduced oxidative damage by
examined; LC modulated the plasma lipid profile and increasing glutathione (GSH) levels and decreasing
increased tissue antioxidant (Yavuz and Kurtoğlu, 2014). malondialdehyde (MDA), a marker for oxidative stress;
LC plays an important role in intracellular energy an increase in GSH protects cells from free radicals
metabolism in two ways. First, it participates in beta- (Fathizadeh et al., 2020). A dose of 3000 mg per day
oxidation by transporting long-chain fatty acids (12 to of this supplement in patients with sepsis contributed
20 carbon atoms) to mitochondria, providing an energy to a reduction in oxidative stress and inflammation
source in the form of acylcarnitine. Second, it reduces the (Keshani et al., 2022). The researchers demonstrated
toxicity of free CoA, which is produced when short-chain that LC supplementation at doses higher than 2 g per
(4-6 carbon atoms) and medium-chain (6-12 carbon day contributed to a reduction in lipid oxidation and
atoms) fatty acids are digested in the mitochondria inflammation and promoted the defence system’s action
(Calabrese et al., 2012). against oxidative stress (Haghighatdoost et al., 2019).
LC is a naturally occurring molecule that aids long-chain A meta-analysis showed that LC reduces inflammatory
fatty acid entrance into cellular mitochondria, providing a cytokines in the blood, such as interleukin 6 (IL-6), CRP,
substrate for oxidation and subsequent energy generation. MDA, and tumour necrosis factor-α (TNF-α), and promotes
The structure of LC improves and preserves cognitive superoxide dismutase (SOD) levels in healthy patients.
performance and contributes to improved cognitive ageing SOD works to reduce the damage of radicals inside the
over time, and multiple controlled human clinical trials cells (Fathizadeh et al., 2020). Lebda et al. (2020) showed
using LC have provided evidence that this substance can that carnitine protects against bisphenol A-induced
improve cognitive function. Furthermore, because LC hepatic toxicity, as it acts as an antioxidant and increases
is a key cofactor in mammalian mitochondrial energy endogenous antioxidative defences. Carnitine contributes
metabolism, it was hypothesised that acute LC treatment to the protection of mitochondria from oxidative stress,
of human tissue cultures would result in observable which causes mitochondrial damage and programmed
improvements in mitochondrial function. LC hydrochloride cell death in various cells. LC contributes to the protection
was given to cultures of SH-SY-5Y human neuroblastoma of mitochondria from oxidative stress, which causes
and 1321N1 human astrocytoma cells cultured in 96-well mitochondrial damage and programmed cell death in
cell culture plates. When human neuroblastoma or human various cells (Elkomy et al., 2020).
astrocytoma cells were exposed to 100 nM (20 µg LC The antioxidant effects of LC include protection
hydrochloride/L) to 100 µM (20 mg LC hydrochloride/L) against lipid, protein, and DNA damage as well as elevated
concentrations of LC hydrochloride, significant increases antioxidant levels (Ribas et al., 2010). LC can also be used as
in mitochondrial function were observed in comparison a metal chelator and a scavenging free radical (Ribas et al.,
with unexposed cells, whereas no significant positive 2012). It increases the antioxidant capacity of cardiac
effects were observed at lower or higher concentrations tissues, which has a cardioprotective effect (Mansour,
of LC hydrochloride (Geier and Geier, 2013). 2013). Moreover, it is essential for lowering CRP, which is
considered a significant risk factor in the development of
CVD (Popović et al., 2014; Amirhossein, 2015).
6. L-Carnitine’s Antioxidant and Anti-Inflammatory
Effects
7. L-Carnitine Clinical Findings
Oxidation is a process that occurs in the cells of the
body. This process results in reactive oxygen species (ROS) Several controlled human clinical studies have found that
and antioxidants; the body is normally able to maintain a LC treatment improves cognition in humans. In a placebo-
balance between ROS and antioxidants, but an imbalance controlled, randomised, double-blinded experiment,
leads to oxidative stress. When ROS production is increased, researchers examined the effects of orally delivered LC
it oxidises biomolecules or modifies proteins and activates on physical and mental exhaustion and cognitive skills
transcription factors and pro-inflammatory genes, causing in centenarians (Malaguarnera et al., 2007). Compared
inflammation. Inflammation causes the body’s immune with those who received a placebo, centenarians who
cells to release cytokines and chemokines to recruit other received LC exhibited significant increases in plasma total
immune cells to the site of oxidative stress (Chatterjee, and free carnitine. LC recipients also showed substantial
2016). In addition, inflammation is the immune system’s decreases in total fat mass and increases in total muscle
response to infection and injury. LC plays an active role in mass compared with placebo recipients. Furthermore,
the work of the immune system by increasing antioxidant by reducing tiredness and increasing cognitive function,
activity and reducing oxidative stress and inflammation this treatment regimen boosted physical and cognitive
(Bellamine et al., 2021). activity capacity.
Previous studies have demonstrated that LC has an In another placebo-controlled, randomised, double-
effective role as an antioxidant and anti-inflammatory, blinded experiment, researchers examined the effects of
preventing the accumulation of the end-products of lipid orally administered LC on the clinical symptoms of autism
peroxidation; when patients with renal diseases were given spectrum disorder (ASD) (Geier et al., 2011). According to
a carnitine supplement for 8 weeks at a dose of 20 mg/kg the researchers’ clinical global impression and the results

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 Biomedical role of L-carnitine

from the Childhood Autism Rating Scale (CARS) and the electrical transport chain of mitochondrial integrity and
Autism Treatment Evaluation Checklist (ATEC), LC treatment contributes to the maintenance of the optimal redox
dramatically reduced the clinical symptoms of ASD, state of the cell by activating antioxidant enzymes and
notably in the areas of cognitive function. In participants non-enzymatic antioxidants. Therefore, the beneficial
diagnosed with ASD who received LC, increased serum effect of LC appeared in the partial recovery of the cardiac
free carnitine levels were significantly associated with muscle with slight congestion in the muscle fibres, as the
clinical improvements in hand muscular strength, cognitive treatment with ASP led to a disturbance of the cardiac
scores, and CARS scores, whereas this association was not muscle fibres and a distortion in the size and shape of its
observed in those who received the placebo. nuclei (Al-Eisa et al., 2018).
LC showed cardioprotection in isoproterenol-treated
rats by reducing the infiltration of inflammatory cells in
8. L-Carnitine and Histopathology myocardial fibres, improving the structure of these fibres,
and significantly decreasing the level of fibrosis resulting
Histological studies have demonstrated the protective from isoproterenol treatment (Emran et al., 2021).
effects of LC on the liver; one of these studies showed a
significant improvement in the liver tissue of mice with
cancer cachexia due to inflammation after treatment
9. L-Carnitine and COVID-19
with LC, as it reduced the appearance of hydropic and
fatty degeneration in hepatocytes, the incidence of LC is a vital and natural component of cells that aids in
cellular necrosis, and the disruption of the hepatic cord fatty acid oxidation in the mitochondria; lowers cholesterol,
(Jiang et al., 2016). LC was also shown to improve fatty LDL, and TAG; and raises HDL. The severity of coronavirus
liver by decreasing the accumulation of lipids in the liver disease 2019 (COVID-19) is related to dyslipidaemia (Wei et al.,
cells of medaka fish (Oryzias latipes)) Fujisawa et al. (2017). 2020). However, new research has demonstrated that LC has
The effect of LC is not limited to the liver; its effect significant antioxidant and anti-inflammatory properties, as
is also observed in the kidneys, where it has shown shown in Figure 3 (Modanloo and Shokrzadeh, 2019). It helps
renoprotective effects in patients with chronic tacrolimus modify the mechanisms of several body systems, such as the
nephropathy (TAC) in the kidney tissue in general and on nervous and immune systems, and reduces inflammatory
mitochondria in particular. The treatment of rats with TAC factors; thus, antioxidant therapy contributes to strengthening
led to an improvement in the infiltration of inflammatory the immune response and improving glutathione levels and
cells, the thickness of the glomerular basement membrane, oxygenation rates in the body (Soto et al., 2020). Therefore,
and an improvement in the renal tubule vacuoles and antioxidant supplementation is recommended as a treatment
tubulointerstitial fibrosis. In addition, LC modified for COVID-19 (Derouiche, 2020)
programmed cell death. At the ultrastructure level, LC treatment of human lung epithelial cells infected with
treatment with LC showed restoration of the mitochondria severe acute respiratory syndrome coronavirus-2 (SARS-
in terms of their number, size, and function. TAC destroyed CoV-2) in vitro has been shown to reduce inflammation
mitochondrial structures and their cristae because of their through the downregulation of angiotensin-converting
high consumption of oxygen, which leads to oxidative enzyme 2 (ACE2), a major host-dependence factor
stress, and treatment with LC led to the elimination of (Bellamine et al., 2021).
oxidative stress (Zheng et al., 2021). No clinical studies have demonstrated a relationship
A study in male rats with cirrhosis showed that the between LC and protection against infection with
administration of LC with branched-chain amino acids coronaviruses, but the protective role of LC in protection
(BCAAs) protected hepatocytes by reducing hepatocyte against COVID-19 was demonstrated using Mendelian
damage through lipotoxicity suppression, enhancement randomisation, in which genetic predisposition reduced
of lipolysis, and an increase in cytoprotective index species susceptibility to COVID-19 when carnitine levels were
(LysoPE). In addition, LC treatment with BCAA contributed elevated (Li et al., 2021).
to the inhibition of the activity of hepatic stellate cells and A considerable percentage of individuals infected with
hepatic macrophages caused by the extracellular vesicles SARS-CoV-2 develop chronic fatigue syndrome, which
of damaged hepatocytes (Tamai et al., 2021). can last for months. Despite this, no specific therapy for
LC led to a significant improvement in the renal post-disease fatigue has been discovered. However, several
histological structure by reducing the incidence of clinical investigations have demonstrated the efficacy of
distortion, inflammation, and interstitial haemorrhage LC in reducing fatigue induced by the treatment of several
resulting from the treatment of male rats with monosodium diseases, such as cancer and multiple sclerosis. As a result,
glutamate (Koohpeyma et al., 2021). it can be regarded a possible alternative for reducing
One of the protective effects of LC is that it contributes COVID-19-induced fatigue, and its use is encouraged in
to the reduction of oxidative stress induced by aspartame future clinical trials to assess its efficacy and safety (Vaziri-
(ASP) in its action as an antioxidant through three Harami and Delkash, 2022).
mechanisms described by Surai (2015). First, its acts as Carnitine modulates the action of inflammatory cytokines,
a free radical scavenger. Second, it inhibits the enzymes such as IL-6 and TNF-α; protects against the side effects of
responsible for the production of free radicals, thus anti-coronavirus drugs; and prevents some damage caused
preventing the formation of free radicals. Third, it works by COVID-19 infection, such as pulmonary dysfunction and
under the conditions of oxidative stress to maintain the cardiotoxicity (Fakhrolmobasheri et al., 2021).

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Al-Dhuayan, I.S.

Figure 4. Factors affecting fatigue after COVID-19 (Rudroff et al., 2020).

Post-infection fatigue occurs often in both viral and several grams; therefore, supplements are frequently
nonviral disorders (Poenaru et al., 2021). As a result, advised for primary and secondary deficits. Supplemental
many patients with COVID-19 experience post-disease consumption of carnitine is generally tolerated because
fatigue. According to Rudroff et al. (2020), fatigue caused it is easily eliminated.
by COVID-19, defined as a decline in physical and mental
activity, may be the result of changes in the central,
peripheral or psychological factors. These factors depend Acknowledgements
on conditional dependencies, such as the tasks a person
performs, the environmental conditions in which the The author declares that this work has not received
tasks are performed, and the person’s physical and mental funding from any funding bodies.
abilities (Figure 4).
Observational studies have revealed that the symptoms
of COVID-19 linger for approximately 21 days from the References
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