L-Carnitine

L-Carnitine (L-3-hydroxytrimethylamminobutanoate) is a naturally occurring amino acid found in animal tissue (meat products) and milk to a degree;^[1] it is also a constituent of human breast milk. It can be synthesized in the body through the two essential amino acids lysine and methionine.^[2] Due to these sources, it is known as one nutrient that affects vegetarians and omnivores differently.

Food tends to have a better intestinal uptake rate on a percentage basis, in the range of 57-84% while supplemental form ranges 14-18% of the dose.^[3] However, this may be due to lower doses being more efficiently absorbed, as average estimated carnitine intake in an omnivore daily is 2-12 micromole/kg daily and vegetarians much lower.^[4][5] For a 200 lb omnivore at the higher end of intake, this equates to 1.09 mg daily. Supplements tend to be in the 250-500 mg range. Thus despite poor oral bioavailability, the absorbed dose is still greater than standard dietary dosages.

L-Carnitine, being a trimethylated amino acid structure, contains a nitrogen molecule in its structure. The related compounds of Acetylcarnitine and Propionylcarnitine are depicted below, and differ slightly:

Carnitine exists in the body in two forms, either L-carnitine or the acetylated form known as Acetyl-L-Carnitine (ALCAR).^[6] The synthesis of these molecules can occur endogenously from the two dietary amino acids L-methionine and lysine, where a peptide-bound lysine is converted to e-N-trimethyllysine via donation of S-adenosyl methionine where it is passively lysed from the peptide; the free e-N-trimethyllysine is then hydroxylated into β-hydroxy-e-N-trimethyllysine and then via the aldolase enzyme it is converted into y-Trimethylaminobutyraldehyde (losing a glycine molecule passively). Finally, a dehydrogenation process (into y-Butyrobetaine) followed by a hydroxylation creates L-carnitine which may then be acetylated to form ALCAR.^[7][8][9] Both hydroxylase enzymes in this process are vitamin C dependent^[10] and deficiencies of vitamin C impair carnitine biosynthesis.^[11]

The rate-limiting step of biosynthesis appears to be either of the trimethyllysine enzymes (aldose and hydroxylase) as dietary y-butryobetaine increases serum carnitine levels to a much higher degree than dietary e-N-trimethyllysine.^[12]

L-Carnitine can be synthesized in the human body from two dietary essential amino acids, L-methionine and lysine. This process involves a few Vitamin C dependent enzymes, and deficiencies of Vitamin C can impair L-carnitine biosynthesis

This internal synthesis is lower in newborns^[13] and thus partially reliant on mother's milk for carnitine intake.^[14] It appears that despite high fluctuations in breast milk carnitine content, that most babies can regulate their systemic carnitine levels; which may be of benefit to vegetarian mothers with lower carnitine stores.^[15][16] Bottle formulations tend to have carnitine supplementation, which can reverse problems associated with a lack of carnitine in infants such as gastrointestinal dysmotility.^[17]

Synthesis of L-carnitine is lower in newborns, although this is covered by both breast milk (provides dietary L-carnitine) and formulations which tend to add L-carnitine to avoid complications of low synthesis

Carnitine status is influenced by both dietary intake of carnitine (via primarily meats and to a lesser extent dairy) as well as in vivo synthesis of carnitine. Carnitine levels are lower in vegetarians and vegans due to no dietary intake, and that endogenous synthesis of carnitine in vegetarians may max out at 1.2umol/kg bodyweight.^[18][19] Dietary intake of carnitine in omnivores can range from 2-12umol/kg, and on average is the source of 75% of total carnitine stores.^[5]

Due to these reasons, subclinical deficiencies of carnitine (low bodily levels) are prevalent in vegetarians and vegans.^[18][20] It has been noted in vegetarian and vegan children as well,^[4] although the degree of concern for children is not significantly greater than for adults.

However this population also has a higher bioavailability of carnitine when ingested.^[5] In a sub-clinical carnitine deficiency state, carnitine absorption in the intestines appears to be upregulated,^[5] although muscular carnitine transport appears to be the opposite, temporarily downregulated in vegetarians.^[21]

Despite the above relative deficiency state, studies on vegetarians and carnitine supplementation are lacking.

It would be prudent for vegetarians to supplement L-carnitine, but there is a lack of human interventions on the subject matter

Related to infants, women appear to experience reduction in plasma Carnitine stores during pregnancy. The 12th week to pregnancy is associated with reduced carnitine stores, and 500mg of L-Carnitine can reduce this decline.^[22] The reason why is not wholly known, but it is suspected to be reduced precursors and less carnitine synthesis.^[23]

Elderly persons may also suffer from a relative carnitine deficiency. Serum levels of carnitine tend to increase until approximately the age of 70, in which case they then decline for unknown reasons; the decline of which is correlated with lean body mass.^[24][25] Supplementation of 2g L-Carnitine is associated with less fatigue and a better body composition in centarians^[25] and can increase muscle function.^[26]

Older people suffering from fatigue or other non-clinical complications would benefit from L-carnitine supplementation.

Carnitine is an essential compound to the performance of the body. It is not a vitamin nor mineral, as the classification for vitamin or mineral denotes that it must be consumed through the diet in order to avoid a disease state. As carnitine is created in the body to a limited degree and no disease state from the diet exists, it is not classified as a vitamin.^[27]

It appears that, relative to optimal whole body levels of carnitine, a subclinical carnitine deficiency may exist in some populations with low dietary intake or otherwise impaired absorption or utilization of carnitine. The populations are listed below in subheadings.

More severe carnitine deficiencies can exist with hindered production paired with a lack of dietary intake. In which symptoms parallel to dementia may be seen as was the case in 8 out of 14 persons noted in this retrospective chart analysis.^[28] Muscle weakness and hepatic dysfunction can also be noted^[29] as well as cardiomyopathy.^[30] For more in depth reading, the following cited book is an in-depth free text.^[31]

Carnitine deficiency rates may increase in some cancer states, and is being investigated as an adjunct treatment for persons with cancer cachexia and low circulating carnitine levels.^[32] A trial of ascending dosages (500mg for 2 days, 1g for 2 days, 2g for 10 days) found that, in persons with both advanced cancer and carnitine deficiency, that supplementation L-carnitine improves fatigue, well-being, and reduces functional impairment associated with cancer^[33][34] and that these improvements may be secondary to increased lean mass.^[35] In this population, dosages up to 3000mg daily have been shown to be safe.^[36]

The cardioprotective medication known as Mildronate is able to reduce L-carnitine levels by 18% after 4 weeks, and thus may induce a relative carnitine deficiency.^[21]

L-Carnitine is seen as the basic form of Carnitine supplementation. As Carnitine has a chiral center, a similar compound called D-Carnitine also exists. One can also find a racemic mixture of both compounds called DL-Carnitine or simple Carnitine. The D-Carnitine molecule cannot fix a carnitine deficiency as it is biologically inert, and may actively work against L-Carnitine in doing so.^[37] The mechanisms of interference include competing for intestinal absorption^[38] and reversing resorption by the kidneys.^[37] In fact, supplementation with D-Carnitine in isolation can reduce body stores by inhibiting dietary usage and induce a Carnitine deficiency.^[39][40] Due to these reasons, the L-Carnitine molecule is highly preferred.

L-Carnitine is the basic form of carnitine supplementation, and is always the base carnitine molecule used since its isomer (D-Carnitine) may actually hinder the effects known to occur with L-carnitine (similar to how L-Arginine is used since its isomer, D-arginine, actually blocks its effects)

Acetyl-L-Carnitine, also known as ALCAR or less frequently as Levacecarnine, is a carnitine molecule bound to an acetyl group. Acetyl-L-Carnitine tends to be seen as the neurological version of Carnitine, and seems to have more interactions in the brain relative to L-Carnitine. In Chronic fatigue, for example, ALCAR can reduce mental fatigue whereas other forms (Propionyl-L-Carnitine) do not significantly do so.^[41]

Acetyl-L-carnitine is another form of L-carnitine that is catered toward neurological effects, and it seems to have some unique properties associated with it that basic L-carnitine does not

GPLC is a Glycine amino acid, bound to a carnitine molecule that is esterified to a short chain fatty acid. When Propinoyl-L-Carnitine reaches the mitochondria, it gets metabolized into L-carnitine and propionyl coenzyme A.^[42][43] Propionyl coenzyme A is relevant as it gets converted into succinyl coenzyme A and thus succinate, which is an intermediate in the TCA cycle. Due to providing succinate as well as carnitine, supplemental GPLC can provide an anaplerotic effect.^[44]

The initial stages of metabolism are undergone by the enzyme Carnitine acetyltransferase, the same enzyme that mediates the breakdown of ALCAR to L-carnitine.^[45]

In practice, Propionyl-L-Carnitine appears to be more effective than L-Carnitine on matters related to blood flow and regulation. The most significant usage is seen with Intermittent Claudication where PLC exerts more benefit than Carnitine even on a molar basis, suggesting synergism between the Propionyl group and the Carnitine group.^[46] GPLC has also been used to increase Nitric Oxide production in sedentary men^[47] and athletes at doses of 3-4.5g daily.^[48]

Glycine propionyl-L-carnitine (GPLC) or propionyl-L-carnitine (PLC) are seen as variants of L-carnitine that can benefit blood flow and pressure to a larger degree than the other forms of L-carnitine

L-Carnitine L-Tartrate is a salt of L-Carnitine bound to tataric acid, and appears to have a quicker absorption rate when measured at 3.5 hours (in pigs) despite no differences in overall bioavailability.^[49] It is used quite frequently in athletic studies due to the quicker influx of L-Carnitine coinciding with activity when taken before.

L-Carnitine L-Tartrate (LCLT) is a form of L-carnitine that is used in a lot of studies in athletes, and it is thought to have a more rapid influx into plasma following oral ingestion (which makes it useful for timing-critical situations, like pre-workout dosing)

L-Carnitine and ALCAR are absorbed in the intestines (jejunum) mostly by the organic cation transporter 2 (OCTN2)^[50][51] which is a sodium dependent transporter.^[38] This transporters takes up L-carnitine molecules, and while ALCAR needs to be deacetylated (removal of the acetyl group) prior to absorption it can readily be reacetylated afterwards.^[38] Alterations in this transporter, such as its increase in states of carnitine deficiency^[52] or its impairment in persons with Celiac disease who are not on a gluten-free diet (and normalization upon switching to a gluten free diet^[53]) determine alterations in L-carnitine absorption.

L-Carnitine is absorbed in the gut via the OCTN2 transporter, and alterations in this transporter determine alterations in L-carnitine absorption. If it is increased, then more is absorbed, if it is impaired or blocked, then less L-carnitine is absorbed

When looking at the overall bioavailability of L-carnitine supplements, there has been contrasting data on whether L-carnitine^[49] or ALCAR^[6][3] are better absorbed relative to the other, although all that has been ascertained is that the isomer of D-carnitine is not absorbed from the intestines.^[38] The bioavailability of carnitine supplements in the dosage range of 1-6g appears to range from 14-18%, which is lower than the bioavailability from lower doses via food products (54-87%)^[54][3] and applies to L-carnitine and ALCAR,^[3] thought to also extend to Propionyl-L-Carnitine.^[55]

When examining variations in the absorption of L-carnitine, it seems that L-carnitine found in food products is absorbed to a better degree than L-carnitine from supplements (regardless of the form used), but supplements are still absorbed to a fairly decent degree

Intradermal delivery of L-carnitine with a microneedling device has been shown to increase bioavailability as much as 2.8x in rats, although this number is subject to vary depending on vehicle and pretreatment.^[56] Topical application doesn't seem to be effective.

Delivery of l-Carnitine via a microneedling defice can increase bioavailability. Topical absorption of L-Carnitine doesn't seem to be a viable method to take L-Carnitine.

Studies in which a dose of 500mg Acetyl-L-Carnitine is given orally result in peak serum levels (T_max) somewhere around 3.1-3.4 hours.^[57][58] Another study with 2g Carnitine, but in three forms (L-Carnitine, Acetyl-L-Carnitine, Propionyl-L-Carnitine) showed L-Carnitine with the highest C_max (84.7+/-25.2 umol/L/h) followed by ALCAR (12.9+/-5.5) and PLC (5.08+/-3.08) although this study may have been influenced by weighting all supplements equally, as ALCAR and PLC have non-carnitine moieties.^[59] Another study looking at L-Carnitine at the same dose (2g) noted the same C_max value of 84.7 ± 25.2 µmol/L.^[57] Serum levels are highly variable due to rapid kidney regulation and conversion between Carnitine and Acetyl-L-Carnitine in the liver, and some long term studies note little increases in serum ALCAR with supplementation.^[60]

The half-life of 500mg ALCAR is 4.2 hours^[58] and has high individual variability.^[59] One study noted the half-life was approximately 60+/-15 minutes after ingestion of 2g L-Carnitine in liquid form.

L-carnitine does not bind to plasma proteins when in circulation^[61] and there does not appear to be too much transportation of L-carnitine into erythrocytes (red blood cells) as studies introducing L-carnitine supplementation do not find any increase in erythrocytic red blood cell carnitine concentrations despite an increase in serum^[62][63] and decreases in serum (seen during dialysis) do not appear to occur in erythrocytes.^[63]

Serum carnitine appears to be regulated in the range of 23–73µmol/L while Acetyl-L-Carnitine appears to be in the range of 3–14µmol/L, both being present independent of dietary supplementation.^[64]

In the tissues themselves, skeletal muscle appears to be the largest pool of bodily L-carnitine by having concentrations up to 126.4mM comprising 98% of bodily stores^[65][6] with the next largest concentrations being the liver (1.3mM) and then the serum and extracellular fluid combined (up to 500µM).^[6]

ALCAR is easily able to cross the blood-brain barrier in humans^[60] via the OCTN2 and B(0,+) transporters.^[66]

On the cell, the uptake of carnitine is one of active transport and is augmented by insulin stimulation and results in increased accrual of dietary L-carnitine^[67] but does not affect basal L-carnitine flux.^[68].

At a cellular level, insulin appears to increase the rate of uptake of L-carnitine into tissue

L-carnitine can be metabolized into trimethylamine, which is then either eliminated or resorbed by the kidneys.^[69]

L-Carnitine is excreted via the kidneys via tubular resorption as the metabolite trimethylamine^[69], which has excretion rates correlated with plasma levels.^[60] Acutely, renal resorption of carnitine and carnitine metabolites is able to regulate serum carnitine levels within the aforementioned range.^[70]

Carnitine can also be excreted fecally via the precurosor turned metabolite y-butryobetaine.^[69] There is possible interaction between enterohepatic recirculation (blood nutrients ejected into the large intestine, taken back up by the blood) and gut microflora in carnitine metabolism, as enzymes that degrade carnitine do not tend to exist in humans.^[71]

On the outer mitochondrial membrane, L-Carnitine works through a subset of the Carnitine acyltransferases called Carnitine Palmitoyltransferases; CPT1 and CPT2 are the most commonly referred to transporters here. L-Carnitine binds to long-chain fatty acids and allows them entry into the mitochondria for the purpose of fat burning.^[72]

On the external side of the inner mitochondrial membrane, L-Carnitine can be converted to and from Acetyl-L-Carnitine by the enzyme carnitine acetyltransferase (CAT); also a subset of 'Carnitine Acyltransferases'.^[73] Specifically, an L-Carnitine as well as a Acetyl-CoA molecule get converted into a CoA molecule and acetyl-L-Carnitine (ALCAR). The Acetyl-CoA donates the acetyl group to carnitine, or retrieves the acetyl group from ALCAR when working in reverse through Carnitine Acetyltransferase.^[73]

On the inner mitochondrial membrane, Acetyl-L-Carnitine is taken up by the transport Carnitine AcylCarnitine transferase (CACT) and can donate its acetyl group to fuel the TCA cycle. This is one of the only two ways the mitochondria can get acetyl groups, the other being synthesis from acetate.^[74]

Citrate (made from the mitochondria) and Acetate (made from cytosolic peroxisomes) can be used to make Acetyl groups to bind to CoA between the mitochondrial membrane walls and create more Acetyl-CoA, to wait for conversion into ALCAR when an excess of L-Carnitine arises.^[72]

L-Carnitine in the mitochondria exists in a balance with acetyl-L-carnitine and acetyl-CoA to regulate mitochondrial activity and fat burning.

L-Carnitine has been implicated in increasing mitochondrial protein count, which is an increase in mitochondrial size and density as well as mitochondrial count (biogenesis).

When placed in rat drinking water, an increase in mitochondrial biogenesis is seen after one month in skeletal muscle.^[75]

Additionally, carnitine supplementation is associted with reducing the decay of mitochondria in muscle after muscular unloading (ie. preserving the increase in mitochondria that exercise induces)^[76] and alleviates the decline in mitochondrial count seen during aging.^[77]

Carnitine supplementation is associated with numerous benefits in aged persons or animals that may or may not apply to younger individuals; it is prudent to give these benefits their own distinction.

The process of aging is highly associated with a decrease in mitochondrial membrane potential, enzyme efficacy, and reductions in the efficacy of enzyme organelles.^[78] In regards to the mitochondria, aging is associated with a decreased ability for oxidative phosphorylation.^[79]

Acetyl-L-Carnitine supplementation can attenuate the decline in mitochondrial membrane potential and cardiolipin (a membrane constituent)^[80] associated with age (and overnutrition).^[81] Cardiolipin is a mitochondria exclusive fatty acid, with numerous vital roles in the mitochondria such as preserving the structure of the Electron Transport Chain and its enzymes.^[74] It has been hypothesized to be a junction point of Acetyl-L-Carnitine and aging, as ALCAR has mechanisms to restore cardiolipin levels.^[82][75][83] However, it does not appear that cardiolipin levels are significantly decreased with aging, at least in regards to the heart.^[84]

At least one cognitive benefit seen from Acetyl-L-Carnitine supplementation (after rat feeding^[85]) was associated with improvements in the cristae of the mitochondria, a structural basis.^[86] When looking into the proteins related to cristae that are affected by ALCAR supplementation in the rat liver,^[87] 10 appear to be affected beneficially (and 1 non-mitochodrial protein, Uricase). Notable proteins include the beta-unit of ATP Synthase, Rhodanese, ALDH1L2, and anti-oxidant enzymes (Glutathione Peroxidase 1 and peroxiredoxin III).^[87] ALCAR did not affect PDCE2, which increased with aging.^[87] Identification of some of these age-related changes have been replicated without ALCAR.^[88]

The former study's benefits were also associated in part to reduced oxidation of RNA, however.^[89] Improvements in mitochondrial cristae and related proteins are not the only mechanism of action.

ALCAR supplementation in rats is associated with 26 proteins in the mitochondria out of 31 that are significantly affected by aging.^[87]

As mentioned before, Acetyl-L-Carnitine supplementation is associated with an attenuated decline in mitochondrial count during aging.^[77]

Mechanically, ALCAR supplementation has the ability to reduce the correlates of aging seen in lab animals, regardless of deficiency state. Whether this translates to a pro-longevity effect in humans is not known for sure, but highly plausible.

The acetyl group of ALCAR (acetyl-L-carnitine) is known to dissociate in vivo and is thought to be able to contribute to acetylcholine synthesis (shown in vitro^[90]).

500mg/kg of ALCAR to mice for 25 days is able to significantly increase serotonin concentrations in the cortex (20%) and cause a trend to increase serotonin in the hippocampus (22%), associated with less turnover of serotonin.^[91]

Noradrenaline concentrations in the hippocampus of otherwise normal mice are increased by 25% after 25 days oral ingestion of 500mg/kg ALCAR.^[91]

500mg/kg of ALCAR daily for 25 days has failed to increase dopamine in the cortex or hippocampus of otherwise normal mice.^[91]

Oral ingestion of 500mg/kg ALCAR daily for 25 days to mice results in GABA concentrations of the hippocampus being reduced by 32% with no influence on GABA concentrations in the cortex.^[91]

There are increase in glucose availability in certain brain regions following 25 days oral ingestion of 500mg/kg in otherwise young mice, such as the hippocampal formation (43%) with a decrease in alanine and lactate as well as the cortex (55%) although no changes in lactate occurred.^[91]

Other energy molecules including inositol (30%), creatine in its phosphorylated form (66%), and phosphorylated adenosine molecules (AMP, ADP, ATP; collectively 23%) were increased over control^[91] and the ATPase enzymes (enyzme that uses ATP to fuel metabolic processes) has been noted to be increased in synaptic membranes following infusions of 30-60mg/kg for 28 days.^[92]

Independent of how the energy is used, oral supplementation of ALCAR has been noted to increase glucose and creatine levels in some brain regions

Intravenous administration of ALCAR results in an increase in cerebral glucose usage within 30 minutes, and when infusing 250-750mg/kg the global increase reaches 13-22% over baseline; this was not replicated with carnitine nor carnitine plus acetate.^[93] When looking at ages, middle and older aged mice appear to be more sensitive to experience an increase in glucose usage than do young mice,^[94] and at least in old mice this has occurred with daily ingestion of 100mg/kg for 28 days.^[94]

The brain region that appears most sensitive to ALCAR increasing glucose uptake is the nuclear accumbens (22-34% increase within 15 minutes of infusion of 500-750mg/kg) locus corealus (48-53%), and corticol amygdala (24-48%).^[93] In contrast, the hippocampus and frontal cortex were not significantly affected in these young mice^[93] although the hippocampus as well as most othe brain regions do appear to be significantly affected in older mice even at low oral intakes of 100mg/kg (20% average increase in the affected brain regions).^[94]

High doses can increase glucose usage in the brain, and older subjects appear to be more sensitive to this increase

In lab animals, ALCAR supplementation has been shown to improve markers of learning in older mice^[95] and, when fed to young mice at low doses (60mg/kg bodyweight, 10mg/kg estimated human equivalent) can alleviate the expected decline in cognition over a lifetime.^[96] ALCAR is currently under investigation for being of potential use in combatting Alzhemier's Disease and Dementia^[97][98] and older mice after ischemia.^[99] Mechanistically, 300mg Acetyl-L-Carnitine per liter drinking water was able to reduce elevated nitric oxide synthase levels in the cortex, which was seen as a sign of aging.^[100]

In regards to human studies on Alzheimer's disease, 1-3g Acetyl-L-Carnitine daily can alleviate the decline in cognition assocaited with Alzheimer's Disease over 6 months^[101][102] and a year.^[103] General cognitive decline (not Alzheimer's) shows similar benefit in aged individuals at 1-2g daily.^{[104][105][106]} Studies in healthy young persons are limited to one, and it came back with no significant differences than placebo; however, it used DL-Carnitine rather than L-Carnitine or its acetylated form.^[107] The benefits seen in these human interventions are not overly potent in any one regard, and fairly spread out across measured parameters of cognition. This suggests the mechanism(s) of action to credit are more general than specific in the brain.

ALCAR supplementation has also been shown to be a mood elevator and alleviate depressive-like symptoms in the elderly,^[108] possibly secondary to benefiting cerebral health.

Although reliable in aged models, its potency is not enough to be warranted as treatment for dementia in isolation.^[109] It is still, however, touted as being a viable conjunct treatment with other neurological protective compounds.

ALCAR appears to be a good therapy for cognitive decline, although its usage in otherwise healthy people has not been well studied

In children (6-13) with ADHD supplemented with 100mg/kg carnitine (maximum of 4,000mg) daily for eight weeks appears to be associated with a significant reduction in symptoms of ADHD varying from 20-65% in the responders; nonresponders to treatment (1-2 out of 13 boys) failed to have an increase in plasma carnitine.^[110]

L-Carnitine seems to be able to stabilize and prolong the activities of intrinsic anti-oxidant enzymes like Superoxide Dismutase, and prevent mitochondrial damage from ethanol in vitro.^[111] Administration of Acetyl-L-Carnitine at 2mg/mL in the water of rats reduced oxidative damage and neuronal loss from alcohol.^[112]

Acetyl-L-Carnitine has also been associated with neuronal protection by attenuating the increase in oxidation and decline in ATP that occurs when neurons are close to beta-amyloid pigmentation, a compound correlated with Alzheimer's Disease and aging.^[113]

Acetyl-L-Carnitine can also induce Heme-Oxygenase 1 in the brain in a dose and time dependent manner,^[114] this was accompanied by an increase in Heat Shock Protein 60 content and NRF2 expression.

In vitro, L-Carnitine has been noted to augment the bone marrow cell proliferative effects of recombinant human erythropoietin (hEPO) at a concentration of 200-400µM^[115] although concentrations below 200µM appear ineffective.^[116] Concentrations of 200µM L-carnitine have been noted to occur in serum following oral supplementation of 15mg/kg oral L-carnitine but not the lower tested dose (1mg/kg).^[117]

L-Carnitine appears to be able to enhance the actions of erythropoietin in vitro, which requires a certain concentration to be met and without activity below this concentration

In aged rats, 150mg/kg L-carnitine (as 195mg/kg L-carnitine L-tartrate) in the drinking water for three months failed to alter red blood cell count or hematocrit relative to control;^[118] this study also failed to find these effects with DHEA sulfate (1mg/kg) supplementation in isolation, yet the combination led to reductions in RBC count and hematocrit relative to control.^[118]

In otherwise healthy but aged rats, supplemental L-carnitine in the water has once failed to influence red blood cell count and function

Long term dialysis is associated with decreased serum L-carnitine concentrations^[119] which are normalized upon supplementation of L-carnitine^[120][121] and treatment of these persons with supplemental L-carnitine appears to promote better responses to exogenous hEPO based on clinical observations mentioned in review.^[122][123]

A pilot study of L-carnitine supplementation at 500mg daily in poor responders to hEPO confirmed an increase in hematocrit and total iron binding capacity, although it was noted that red blood cell carnitine concentrations were not reduced during serum L-carnitine deficiency and were unaltered despite better clinical responses.^[63] Since this study numerous trials have been conducted and subject to meta-analysis.

The first meta-analysis to be published assessing 18 randomized trials (total participants 482) noted a stastistically significant increase in hemoglobin and reduced dose of hEPO required for maintenance dialysis,^[124] and the second meta-analysis comprising all studies using oral L-carnitine supplementation for longer than two weeks (49 trials)^[125] confirmed a decrease in inflammation as assessing C-reactive protein levels (in these persons, a biomarker for all cause mortality^[126]) but failed to confirm any benefit on hematocrit, red blood cell count, or the maintenance dose of hEPO required.^[125] This latter meta-analysis also reported an improved quality of life with supplementation of L-carnitine based off of the results of six (out of ten) trials with combinable continuous data, but did not draw conclusions due to paucity of data.^[125]

Serum L-Carnitine is reduced in the state of hemodialysis-induced anemia, and the reduced responsiveness to exogenous erythropoietin seen in this state is thought to be attenuated by L-carnitine supplementation. While supplementation of L-carnitine during dialysis may be beneficial, the benefits to erythropoietin responsiveness are not fully established

L-Carnitine supplementation to mice (1.3% of drinking water, assuming 5mL water intake this is a human equivalent of 208mg/kg converted from the mouse dose of 2,600mg/kg) was able to produce trimethylamine oxide (TMAO) via an intestinal microbial dependent pathway and produce atherosclerosis in ApoE^-/- mice; TMAO production, but not atherosclerosis, was confirmed in non-vegan humans.^[127]

It is unclear how much concern should be paid to this information due to the high dose used, but it seems unlikely that carnitine could cause atherosclerosis in supplemental doses.

ALCAR in conjunction with ALA can potentially reduce hypertension in via their combined anti-oxidant and pro-energetic effects^[128] as well as insulin resistance and glucose tolerance in those with compromised cardiac health^[129] with minimal to no side-effects at the dosage of 2g a day. At this dose of 2g daily, it has been implicating in reducing blood pressure in persons with poor glucose tolerance by almost 10 points systolic, with some decrease in diastolic as well.^[130]

A dose of 4.5g GPLC has been shown to increase nitric oxide levels after 28 days of supplementation in some persons,^[48] and does so at a dose of 3g as well.^[47]

ALCAR may benefit blood pressure in unhealthy people (metabolic syndrome, high blood pressure). It has the mechanisms to improve blood pressure independent of a disease state via nitric oxide, but it is unclear how it affects blood pressure in individuals with normal blood pressure.

Carnitine, in the form of Propionyl-L-Carnitine (PLC, or GPLC if bound to Glycine), has been shown to improve symptoms of intermittent claudication. PLC supplementation at a dose of 1-3g a day seems to reliably increase maximum walking time in persons suffering from intermittent claudication^{[131][132][133]} and improve quality of life.^[134] The benefit does not appear to be dose dependent, and seems to benefit persons with more severe symptoms to a greater degree than persons with lesser symptoms.

PLC aids peripheral arterial diseases in general as it increases peripheral microcirculation.^[135][136] In persons with peripheral arterial diseases, PLC supplementation can increase strength and exercise performance^[137] although exercise itself can also be seen as therapeutic.^[138]

Quite promising for periphery artery disease and intermittent claudication

During aging, defects in oxidative phosphorylation occur exclusively in Interfibrillar mitochondria, located between myofibrils.^[139][140] Due to substrate poorly oxidized when introduced into complexes I, III, and IV and not alleviated by uncoupling it appears the aging 'defect' associated with cardiac mitochondria is located in the Electron Transport Chain.^[74] Enzymatic activity of complexes III (through cytochrome C binding) and IV also appear to be decreased during cardiac aging.^{[139][141][142]}

It appears these damages may be secondary to cardiac Ischemia.^[74] Ischemia causes damage to the Electron Transport Chain after 10-20 minutes via reducing activity of complex I^[143] and reducing phosphorylation at complex V and adenine dinucleotide translocase.^[144][145] Complex III^[143] and IV^[146] are hindered at longer periods of Ischemia. It appears that the general process of Ischemia hits elderly persons harder than youth^[147] despite some level of damage at both ages.^[148]

Acetyl-L-Carnitine is proposed to target these defects its various mitochondrial benefits, discussed elsewhere. One such benefit is seen when aged rats were given a bolus of Acetyl-L-Carnitine 3 hours before cardiac Ischemia, and suffered less damage.^[149] The same benefits were not seen with adult hearts subject to Ischemia, and the damage induced to aged hearts defaulted to similar levels as adult hearts.^[149][74]

Another possible mechanism is increasing levels of CPT1 in the myocardium, without affecting overall carnitine levels.^[150] A decline of this rate-limiting step is seen during aging, thus upregulating it may attenuate changes seen with aging. It has been noted in human hearts that less fatty acid oxidation occurs with aging, causing a shift towards cardiac glucose metabolism^[151] which are thought to be due to less CPT1 activity.^[152][153]

Acytel-L-Carnitine has the mechanisms to benefit the heart muscle itself during aging and looks promising as a cardiac anti-aging compound. Practical relevance is not known at this time.

One meta-analysis assessing the role of L-Carnitine in secondary prevention of cardiovascular disease^[154] assessing 13 trials conducted on the topic in persons who sufferred a myocardial infarction^{[155][156][157][158][159][160][161][162][163][164]} noted that supplemental L-Carnitine was associated with a 27% reduced risk of all-cause mortality (RR 0.78; 95% CI of 0.60-1.00) due to large reductions in ventricular arrhythmias (62%; RR of 0.35 and 95% CI of 0.21-0.58 derived from 5 trials) and angina (40%; RR of 0.60 and 95% CI of 0.50-0.72 with data derived from two trials) but no protective effect against heart failure (6 trials; 95% CI of 0.67-1.09) nor myocardial reinfarction (4 trials, 95% CI of 0.41-1.48).^[154] The authors hypothesized that Carnitine would be effective in persons with acute myocardial infarction and stable angina.^[154]

The supplement appears to confer protective effects to people who have experienced a heart attack in the past

Despite its high prevalence and dependency for beta-oxidation, dietary and supplemental L-carnitine does not seem to positively influence fat metabolism unless the subject is in an otherwise deficient state.^[165][166] Deficient states may include veganism and vegetarianism as well as older age, or conditions with a low dietary carnitine intake (from meats) or impaired carnitine utilization.^[167] Basically, somebody who falls into one of the previously outlined deficiency states may benefit from carnitine supplementation in regards to fat loss.

Standard supplement interventions looking at L-Carnitine and either fat mass or body weight fail to note any significant effects in rats^[166][165] or in obese women with 2g of L-Carnitine daily and aerobic exercise.^[168]

On a cellular level, the presence of Carnitine in the form of supplementation does induce enzymatic changes that do make the potency of the beta-oxidation pathway increase when paired with exercise.^[169]

During exercise, L-Carnitine (as L-Tartrate) supplementation may influence substrate utilization slightly but does not appear to influence overall fat and glucose oxidation rates,^[170][171] Glycogen depletion rates are also not affected.^[172] After exercise a slight trend towards fat oxidation (as assessed by respiratory quotient) has been noted.^[173]

In rats, exceptionally high levels of L-carnitine supplementation results in a phenomenon called 'Fatty acid dumping', in which Acetyl groups from fatty acids are excreted in the urine in the form of acylcarnitine and acetylcarnitine rather than Co2 in the breath.^[174] This phenomena occurs secondary to carnitine's ability to shuttle acyl- and acetyl- groups out of the cell and into plasma, as they may build up during fat burning in the cell.^[175] This shuttle of by-products out of the cell is thought to play a role in insulin sensitivity, as build-up of byproducts is associated with insulin resistance.^[176]

This effect is drastically enhanced during co-ingestion of choline and caffeine, but although it can increased the caloric content of urine (like ketone bodies) it has yet to ultimately be shown as causative for fat loss in humans and animals.^[174]

L-Carnitine has many mechanisms by which it can theoretically increase the rate of fat loss, yet it doesn't seem to actually induce or augment fat loss when supplemented. The exception to this is in a deficiency state, in which L-carnitine supplementation will restore hindered fat burning potential.

A 24-week study using 2g of Acetyl-L-Carnitine daily was able to increase the glucose disposal rate in persons at risk for diabetes, from 4.89+/-1.47 to 6.72+/-3.12 mg/kg/min.^[130] This was the first study to note oral administration of ALCAR causing increased glucose disposal, as IV studies have shown benefit in persons with both forms of diabetes.^[177][178] In fact, carnitine repletion therapy (for deficiencies) tends to warn about possible hypoglycemia from glucose disposal.^[31]

Insulin sensitivity can be increased with Carnitine supplementation in obese persons and those with impaired glucose tolerance, such as pre-diabetes and those with metabolic syndrome.^{[179][180][130]} Improvements in sensitivity have been noted as quickly as 10 days with 2g Carnitine supplementation, although this particular study required a hypocaloric diet in conjunction with Carnitine supplementation.^[179]

At least one study noted that 2g Carnitine supplementation can reduce the risk of gestational diabetes by preventing an increase in plasma FFA, which is seen as the main cause of gestational diabetes and insulin resistance.^[181]

The mechanisms by which it increases muscular uptake of glucose is via stimulation of AMPK-mediated glucose uptake^[182] Carnitine supplementation can also downregulate TNF-a's suppressive effects on glucose uptake.^[183]

Mechanisms of increasing insulin sensitivity include shuttling acyl and acetyl groups out of a cell and into plasma, to be excreted in the urine; a process known as fatty acid dumping.^[175] L-Carnitine could also simply shuttle these acyl groups into the mitochondria to be burnt during beta-oxidation (fat burning).^[184] Build-up of these groups in a cell may lead to skeletal muscle insulin resistance, and thus carnitine transport would act as a therapeutic measure.^[176][184]

Carnitine appears to be able to increase glucose disposal, and can increase insulin sensitivity in those with impaired glucose metabolism (whether it increases insulin resistance in healthy people is less clear)

Insulin secretion is able to increase carnitine deposition in muscle tissue via stimulating the organic cation transporter OCTN2, which brings carnitine into cells.^[185] This usually occurs during hyperinsulinemia (700pM or more) which occurs after food, as baseline insulin secretion does not influence carnitine deposition.^[68]

Interestingly, this level of insulin may be reached during insulin resistance (pre-diabetes) and thus carnitine can act as a glucose disposal agent independent of meals. This may help to explain differences seen in persons with metabolic syndrome and healthy subjects.

High insulin levels increase deposition of carnitine into muscles, and thus it would be good to take Carnitine with carbohydrates. Those with high fasting insulin levels may not even need carbohydrates for this benefit.

Looking at power output specifically, results are a bit mixed. In general, studies suggest that L-Carnitine supplementation in all its forms does not increase acute power output when ingested once before exercise or as a daily supplement.^[186][187] One study noted slight increases in sprint power and increased work capacity, possibly secondary to reduced lactate build-up following 4.5g GPLC once before exercise.^[188] Another study noted that over a supplementation period of 28 days noted this increased power during sprints occurred at 1.5g GPLC, whereas 3-4.5g was suppressive of power output.^[189]

Markers of purine metabolism and circulating cystolic proteins (creatine kinase, myoglobin, fatty acid binding protein) are reduced after 2g L-Carnitine L-Tartrate for 3 weeks in resistance trained men.^[190][191] This has been replicated with just L-Carnitine as well.^[186] A possible mechanism is enhancing oxygenation of muscle^[192] and thus recovery from hypoxic (anaerobic) exercise.^[191]

Carnitine supplementation, as either Acetyl-L-Carnitine or GPLC, has been shown to increase Nitric Oxide levels^[47] or plasma nitrate/nitrite^[193][48] at 1-3g daily independent of exercise, which could possibly be connected to the previously mentioned increased oxygenation of muscle tissue.

In comparing 1g and 2g L-Carnitine (as L-Tartrate), both doses are effective in reducing markers of muscular damage despite the higher dosage causing greater serum increases of Carnitine.^[194] One study that looked as to whether these reductions in muscle damage affected acute recovery times noted no differences between placebo and 2g L-Carnitine when two anaerboic cardio sessions were separated by 3 hours.^[195]

Carnitine supplementation seems to reduce markers of muscle damage after anaerobic exercise, possibly through enhancing oxygenation of tissue when oxygen is lacking. This mechanism might also explain the greater work volume seen in one study.

In subjects who experience glycogen depletion from exercise, blood acylcarnitine concentrations significantly spike in the supplemented persons (3g daily for seven days) relative to controls yet this was not met with any changes in self-reported fatigue or fat oxidation rates.^[196]

In looking at human interventions, L-Carnitine at 15g can promote aerobic endurance^[197] whereas smaller doses (2g) are ineffective.^[198] 3g of Glycine-Propionyl-L-Carnitine was also seen as ineffective.^[187] Increased time to fatigue (endurance) has been noted at smaller dosages (20mg/kg bodyweight) but in renal patients, which may not apply to healthy persons.^[199]

High dose L-carnitine in rats in conjunction with dietary caffeine and choline (to promote carnitine accumulation in tissue^[200]) appears to increase VO2 max at high doses, 5g/kg ALCAR in the rat diet.^[174]

There is not a consensus that moderate to high doses of L-Carnitine improve athletic performance^[201][202] although the mechanisms by which athletic performance can be improved exist with carnitine supplementation.^[203]

Studies show mixed results. It doesn't seem to reliably offer aerobic exercise benefits after common dosages and might increase sprint performance (both max speed and volume done). It seems a bit more reliable in increasing work volume at 1.5-2g daily, but further study is needed.

Supplemental L-Carnitine L-Tartrate at 2g daily has been shown in vivo to increase the density of Androgen Receptors in muscle cells over 21 days.^[204] Although this mechanism would not increase testosterone levels per se, it may increase the effects of testosterone as they are vicarious through its receptors.

2g L-Carnitine L-Tartrate does not further increase testosterone levels that are induced by exercise after 3 weeks supplementation in healthy males^[191] and still does not increase test in a population of men going through andropause (male equivalent of menopause) despite controlling other symptoms.^[205] In one rat study, it was noted that although Acetyl-L-carnitine did not increase testosterone that it prevented the decline of testosterone associated with chronic stress.^[206]

Supplementation may be a decent adjunct to a testosterone boosting protocol, but aside from a lack of evidence on its mechanisms, it does not seem to boost testosterone itself.

L-Carnitine L-Tartrate, at 2g daily over 3 weeks, was able to increase levels of IGF Binding Protein-3 that are induced by exercise for about 180 minutes. This theoretically may increase the effects of IGF-1 and IGF-2 by giving them more time in the blood.^[191]

Supplementing ALCAR into the feed of animals increases ambulatory activity (defined as overall distance traveled) in both young and old rats, although the increase is typically much greater in older rats.^[80][209]

In otherwise healthy humans, Acetyl-L-Carnitine at 2g (paired with another 2g of Propionyl-L-Carnitine) in older men was able to decrease fatigue while alleviating symptoms of 'andropause' (erectile dysfuntion).^[205] Older individuals still (71-78) experience reductions in fatigue, as well as improvements in sleep disorders related to fatigue and reductions in post-exercise fatigue.^[210]

It has been shown to decrease fatigue in a human population of hepatic encepalopathy, secondary to reducing ammonia levels which tend to induce fatigue,^[211] reduce quality of life,^[212] and hinder cognition.^{[213][214][215]} As these benefits are seen by therapeutically reducing ammonia, they are unlikely to translate into other disease states. The connection of anti-fatigue is coincidental.

L-Carnitine supplementation has been shown to improve fatigue in persons with Celiac disease related fatigue, but requires adherence to a gluten-free diet prior to intervention to restore intestinal uptake of carnitine.^[53] The mechanism of this improvement in fatigue is not known.

As an adjunct therapy for cancer, L-Carnitine may decrease fatigue indirectly through increased lean mass and reducing cancer cachexia.^{[35][216][217]} Carnitine deficiency is prevalent among some forms of Cancer^[34] and reversing this deficiency can theoretically reverse fatigue.^[36] That being said, not all studies come back positive.^[33] Doses tend to be around 2-3g daily of L-Carnitine or Acetyl-L-Carnitine.

L-carnitine has been actively explored in humans as a way to combat cachexia (muscle wasting) and fatigue associated with cancer ^[32]. A one week phase I/II open label study of L-carnitine supplementation showed improvements in fatigue, mood, and sleep ^[36]. Furthermore, a randomized phase III clinical trial with patients with advanced cancer showed significant improvements in fatigue ^[218], however a followup phase III study showed that L-carnitine supplementation alone had an insignificant effect on fatigue ^[219].

Interestingly, when L-carnitine was supplemented in combination with medroxyprogesterone or megestrol acetate, eicosapentaenoic and thalidomide, there was a significant improvement in patient fatigue, body composition, and appetite ^[219].

Carnitine is not really a cancer preventative agent, but is being studied for its inclusion into chemotherapy to assist in combating the side-effects cachexia and suppressed appetite. Effects are possibly related to carnitine deficiencies that occur in some cancer metabolisms.

Carnitine, as L-Carnitine L-tartrate, has been shown in vitro to enhance hair follicle growth by simultaneously enhancing growth and attenuating apoptosis (cell death).^[220] It seemed to be effective at a concentration of 0.5uM and 5uM.

One study using a compound formulation including L-carnitine given to subfertile men has noted improvements in sperm parameters.^[221]

Alpha-Lipoic acid and Carnitine are mitochondrially related molecules, as acetyl groups shuttled into the inner mitochondrial membrane can be used for lipoic acid synthesis.^[222]

Although an oral dose of ALCAR and ALA is associated with decreased mitochondrial oxidation^[209] ALCAR alone is associated with more oxidation secondary to increased metabolic activity.^[80] This associated is dose dependent, as low doses in isolation may not increase oxidation while higher dosages do.^[85]

Choline, when supplemented at 20mg/kg bodyweight, seems to preserve L-carnitine status in humans and guinea pigs (but not rats) by decreasing urinary excretion rates and increasing deposition of L-carnitine in muscle tissue.^[223][224] However, at least one study noted that the effects of carnitine were not furthered by this increased deposition.^[225]

Choline and L-Carnitine ingestion also seem to be able to reduce fat mass in rats^[226] and humans^[227] but does not seem to be augmented with exercise nor overly significant, which may be due to the low doses used in the human study (0.68g L-carnitine L-tartrate and 0.94g choline bitartrate).

In isolated neurons, choline and carnitine appear to show synergism in acetylcholine production. It was unable to stimulated acetylcholine production in isolation, but with choline at 20uM it increased production by 36%.^[228] One rat study, however, noted augmentation in adult rats (+18%) but inhibition in suckling rats.^[229] No human studies exist on this topic.

Genistein, one of the three soy isoflavones, is able to increase the rate limiting enzyme in beta-oxidation (fat-burning) called Carnitine Palmoyl Transferase 1.^[230] Carnitine is able to do this as well, and the combination is synergistic rather than additive in hepatocytes.^[231] The combination has shown efficay in a rat study in upregulated CPT-I by 40% and Coenzyme A Synthetase by 50%, also synergism was not noted in vivo.^[232]

CoEnzyme Q10 is a mitochondrial nutrient, important in the Electron transport chain. There is evidence that both CoQ10 and Carnitine are deficient in persons with Heart Failure, and a combination of the two has been shown to increase quality of life and decrease inflammation over 12 weeks.^[233]

Alcohol, or drinking ethanol, is a nice way to relax. That being said, Acetyl-L-Carnitine seems to confer protective effects against ethanol-induced neurodegeneration. Acetyl-L-Carnitine is used more in research on this topic due to its ability to cross the blood-brain barrier easier.

When incubated at 2ng/mL drinking water in rats (a rather low human dose equivalent) it appears to protect the brain from a degree of oxidative damage induced from alcohol.^[112] One study in alcoholics over 90 days using 2g Acetyl-L-Carnitine found significant improvements in all cognitive functions measured, although this population had cognitive deficits at the onset of the study.^[234]

The mechanism of anti-oxidation may be stabilization (prolonging the efficacy of) an intrinsic anti-oxidant enzyme known as Superoxide Dismutase.^[111]

Alcohol appears to be able to reduce glucose uptake into the brain via reducing the activity of the GLUT1 transport,^[235][236] the inhibition appears to be at the genetic level in reducing transcription of it rather than competitive inhibition (blocking). GLUT1 is the rate-limiting and main transport for glucose at the level of the Blood Brain Barrier.^[237] Acetyl-L-Carnitine may alleviate these effects.^[238] Co-incubation of the two (ethanol at 50uM, ALCAR at 200uM) prevents the downregulation of GLUT1 transporters fully, and the same effect was seen in vivo for rats.^[238] Acetyl-L-Carnitine also reduced the alcohol-induced increase in Blood Brain Barrier permeability.^[238]

One small pilot study on rugby players (n=5) on a cycle ergometer test where after a 45 minute prefatigue (60% VO₂ max) it was followed up with an 80% VO₂ to exhaustion, the coingestion of L-Carnitine (15g) with caffeine (5mg/kg) improved physical endurance to a greater degree than either agent alone and appeared to be synergstic in doing so.^[197]

It has been noted that DHEA can increase sensitivity of red blood cells to oxidative stress at concentrations thought to be relevant to supplementation^[239] (higher concentrations of 2mM induce nonoxidative cell death, but are not thought to be practically relevant to oral supplementation of standard doses^[240]) while L-carnitine appears to exert antioxidative effects at the level of the red blood cell membrane^[241] which may result in an increase in cell survival in vitro.^[242]

One study in rats tested both L-carnitine L-tartrate (195mg/kg in the drinking water) and DHEA sulfate (1mg/kg) noted that, while neither agent alone influenced red blood cells, that the combination led to a minor reduction in both red blood cell count (12.1%) and hematocrit (9.7%) despite hemoglobin and other erythrocytic indices being unaffected in all groups.^[118]

It is possible for L-carnitine and DHEA to have interactions at the level of the red blood cell, although the clinical relevance of this information (beneficial, inert, or harmful) is not yet known and more data required

A safety study on L-Carnitine L-Tartrate investigating 3g daily for 3 weeks in 21 healthy men noted no aberrations to enzyme or blood parameters, and suggested its safety as an oral supplement.^[243]

At least in carnitine deficiency states (which may not be fully applicable to healthy humans) the recommended dosage of Levocarnitine (L-Carnitine) is 100-400mg per kilogram bodyweight

In general, there does not appear to be any toxicity associated with the standard supplemental dosages of carnitine

A few studies have noted a benign adverse effect of 'odd smell', which is said to be due to the formation of trimethylamines; it has occurred at a frequency of 4%.^[110]

Some authors have stated (unpublished data) that this smell is attenuated with riboflavin supplementation.^[110]