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L-Carnitine and the related compound Acetyl-L-Carnitine (ALCAR) are mitochondrial health and bioenergetic compounds, able to alleviate the effects of aging and disease on the mitochondria and increase the potential of the mitochondria to burn fat.
Although the theory behind ALCAR supplementation in fat burning is great, studies in which ALCAR is given in isolation to humans do not show the best results in fat loss. Results that are seen are typically due to the increased activity done by the subjects from the increased energy they get from ALCAR supplementation.
ALCAR has been shown to be very effective in alleviating what can be seen as the side-effects of aging (neurological decline, chronic fatigue) as well as being a very safe method of improving insulin sensitivity and blood vessel health in those that have weakened or delicate cardiac health. It also exerts beneficial effects on neurons, repairing them from damage induced by some states such as diabetes (diabetic neuropathy).
ALCAR is also typically used as a brain booster due to its effects at increasing alertness, mitochondrial capacity, neuronal support and by acting as a cholinomimetic (increased acetylcholine levels).
The effects of ALCAR supplementation benefit everybody, but are much more effective in older individuals and those with metabolic abnormalities such as dementia, metabolic syndrome, or chronic fatigue syndrome.
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Acetyl-L-Carnitine, ALCAR, Acetylcarnitine, L-Carnitine, L-Carnitine-L-Tartrate, LCLT, Glycine Propionyl-L-Carnitine, GPLC, Levocarnitine, Levacecarnine, L-3-hydroxytrimethylamminobutanoate
Carnosine (the product of Beta-Alanine)
It is recommended to supplement with the form Acetyl-L-Carnitine (ALCAR) for best results.
Mitochondrial support and neuron health have been found to be dose-dependent. 750mg of ALCAR will aid these functions effectively although for a neurological boost 2,000mg of ALCAR can be used in either 2 divided doses or one acutely.
Animal studies have used doses up to 500mg/kg bodyweight with no observable side effects.
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The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect L-Carnitine has in your body, and how strong these effects are.
|Grade||Level of Evidence|
|A||Robust research conducted with repeated double blind clinical trials|
|B||Multiple studies where at least two are double-blind and placebo controlled|
|C||Single double blind study or multiple cohort studies|
|D||Uncontrolled or observational studies only|
|Level of Evidence ||Effect||Change||Magnitude of Effect Size ||Scientific Consensus||Comments|
|B||Treatment of Hepatic Encephalopathy|
Cognitive side effects of hepatic encepalopathy are alleviated with carnitine supplementation, notably fatigue and cognitive performance.
A decrease in ammonia has been noted, and appears to influence both hepatic encephalopathy as well as persons with no significant liver damage
A decrease in blood glucose has been noted with carnitine supplementation
Carnitine appears to be somewhat effective in reducing fatigue in elderly persons with low muscular endurance and perhaps in chronic fatigue syndrome; there is insufficient... show
|B||Muscle Carnitine Content|
Unreliable and mixed effects, but some studies do note that muscular carnitine levels can be increased with carnitine supplements.
Highly mixed effects on power output, with mostly no significant influence but a possible increase in mean power output occurring in short-term anaerobic endurance exercise... show
Lactate production appears to be decreased in studies that note an increase in muscular carnitine stores, although the decrease is not overly notable
Biomarkers of muscle damage including creatine kinase and muscle soreness are both fairly reliably reduced following ingestion of carnitine and pairing with exercise
A decrease in the exercise-induced increase in MDA levels is seen with carnitine supplementation, possibly secondary to reducing damage to muscle tissue. The degree of... show
The reduction in MDA that occurs during exercise may also occur at rest, suggesting a per se effect
For the most part, there does not appear to be a significant influence of carnitine on total cholesterol levels
|B||Symptoms of Intermittent Claudication|
Symptoms of intermittent claudation are notably reduced with L-Carnitine supplementation (the rate of improvement over time, as assessed by walking distance, seems to be... show
Carnitine at 3g daily appears to increase sperm quality mostly related to sperm morphology; there are mixed effects on sperm motility
More evidence than not suggest no significant influence on low intensity and high duration cardiovascular exercise
There appears to be a fat reducing effect of L-Carnitine supplementation, but this may be limited to elderly persons; limited studies in otherwise healthy youth and adults... show
An increase in insulin sensitivity appears to exist with carnitine supplementation, and at least once has been noted in otherwise healthy lean males. This may be secondary... show
A decrease in heart rate has been noted associated with supplementation
|C||Symptoms of Autism|
High dose carnitine (50mg per kilogram) appears to reduce some symptoms of autism as assessed by rating scales; notable due to the rarity of a supplement towards this goal
No significant changes in subjective well being associated with carnitine intake
Improvements in general cognitive capacity has been noted in elderly persons and in disease models (hepatic encepalopathy); lack of literature on otherwise healthy youth
|C||Anaerobic Running Capacity|
An increase in anaerobic cardiovascular exercise has been noted with carnitine ingestion
No detectable influence on VO2 max associated with carnitine supplementation
|C||Rate of Percieved Exertion|
A reduction in the rate of perceived exertion appears to exist following carnitine supplementation
A decrease in uric acid has been noted
The decrease in muscle soreness appears to correlate with the reduced muscle damage
No significant alterations noted
|C||IGF Binding Protein|
An increase in IGF binding protein (3) has been noted following carnitine supplementation in otherwise healthy youth
No significant changes in IGF-1 seen with carnitine supplementation; IGF-2 also appears unaffected
A decrease in muscle oxygenation has been noted during occlusion, but not during squat exercise; practical significance of these results unknown
|C||Androgen Receptor Density|
At least one study has noted an increase in androgen receptor density in skeletal muscle tissue
An increase in nitric oxide has been noted, thought to be secondary to increases in plasma nitrate
No significant influence on triglycerides
No detectable influence on LDL-C levels
No significant changes in HDL cholesterol seen with supplementation
Plasma Nitrate appears to be increased following carnitine ingestion, although not to the same degree as nitrate supplementation itself
|C||Symptoms of Fibromyalgia|
Fibromyalgic symptoms are reduced with carnitine ingestion
A reduced rate of relapse and alcohol cravings was noted with ALCAR ingestion relative to placebo
|C||Symptoms of Multiple Sclerosis|
Some symptoms associated with multiple sclerosis are noted to be reduced with carnitine ingestion.
|C||Symptoms of Hyperthyroidism|
Some symptoms of hyperthyroidism are reduced following carnitine supplementation
No significant influence on TNF-a
Increases in blood flow appear to occur following carnitine supplementation, which may be related to the increases in nitrate
An increase in lean mass has been noted in elderly persons. This may not apply to lean healthy individuals, and no research assesses youth
Rates of fat oxidation appear unaffected following carnitine supplementation
No significant influence on metabolic rate noted with carnitine supplementation
|C||Anti-oxidant Enzyme Profile|
An increase in all three main enzymes (SOD, glutathione peroxidase, catalase) has been detected following ingestion of carnitine
A decrease in liver enzymes has been noted in a model of hepatic encepalopathy, a per se reducing effect is uncertain
Possible antiinflammatory effect on exercise-induced inflammatory biomarkers
An increase in adiponectin has been noted
May reduce blood pressure
|C||ADHD in Children|
At least one study has noted reduction in ADHD symptoms in children
Fasting insulin has been noted to be decreased in diabetics given carnitine
One study has noted an improvement in erections in persons thought to have impaired blood flow
Reduction in general oxidation seems to be secondary to antioxidant enzyme induction
An increase in attention has been noted to be secondary to reductions in the symptoms of chronic fatigue
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L-Carnitine (L-3-hydroxytrimethylamminobutanoate) is a naturally occurring amino acid found in animal tissue (meat products) and milk to a degree; 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. 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. However, this may be due to lower doses being more efficiently absorbed, as average estimated carnitine intake in an omnivore daily is 2-12mcg/kg daily and vegetarians much lower. For a 200lb omnivore at the higher end of intake, this equates to 1.09mg daily. Supplements tend to be in the 250-500mg 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 as two main forms in the body, carnitine itself and its acetylated version Acetyl-L-Carnitine (ALCAR). They act as endogenous vitamin-like compounds.
It is created in the liver from the two amino acids methionine and lysine. Specifically, a peptide-linked lysine molecule is converted into a peptide-linked e-N-trimethyllysine molecule via the enzyme S-adenosyl-L-methionine and then passively hydrolyzed from the peptide chain. It is then hydroxylated (via e-N-Trimethyllysine hydroxylase) into B-hydroxy-e-N-Trimethyllysine.
Via its aldolase enzyme, it converts into y-Trimethylaminobutyraldehyde and loses a glycine amino acid passively.
Both hydroxylase enzymes are Vitamin C dependent and deficiencies of vitamin C impair carnitine biosynthesis. 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.
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.
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. Muscle weakness and hepatic dysfunction can also be noted as well as cardiomyopathy. For more in depth reading, the following cited book is an in-depth free text.
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. Dietary intake of carnitine in omnivores can range from 2-12umol/kg, and on average is the source of 75% of total carnitine stores.
Due to these reasons, subclinical deficiencies of carnitine (low bodily levels) are prevalent in vegetarians and vegans. It has been noted in vegetarian and vegan children as well, 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. In a sub-clinical carnitine deficiency state, carnitine absorption in the intestines appears to be upregulated, although muscular carnitine transport appears to be the opposite, temporarily downregulated in vegetarians.
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
This internal synthesis is lower in newborns and thus partially reliant on mother's milk for carnitine intake. 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. Bottle formulations tend to have carnitine supplementation, which can reverse problems associated with a lack of carnitine in infants such as gastrointestinal dysmotility.
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. The reason why is not wholly known, but it is suspected to be reduced precursors and less carnitine synthesis.
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. Supplementation of 2g L-Carnitine is associated with less fatigue and a better body composition in centarians and can increase muscle function.
Persons in their later years who may be suffering from fatigue or other non-clinical complications would benefit from some L-carnitine supplementation.
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. 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 and that these improvements may be secondary to increased lean mass. In this population, dosages up to 3000mg daily have been shown to be safe.
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.
Carnitine in food sources tends to have higher bioavialability (54-87%) than supplementation of L-Carnitine at 14-18%. This general trend of much lower bioavailability from supplementation holds true for Acetyl-L-Carnitine and studies in animals suggest it would hold true for Propionyl-L-carnitine.
When ingested orally, they are readily absorbed in the jujenum almost exclusively by sodium-dependent facilitated diffusion via the Organic Cation Transporter 2 (OCTN2), a sodium dependent facilitated diffusion. Some studies note Acetyl-L-Carnitine as having higher bioavailability relative to L-Carnitine while some other studies note the opposite. Regardless, Acetyl-L-Carnitine has to be deacetylated prior to absorption only to have a certain amount reacetylated after absorption. D-isomers of Carnitine do not appear to be taken up in the gut.
In some disease states, intestinal OCTN2 transporters are diminished or eliminated. One such case is Celiac disease. Interventions in celiac disease require a gluten-free diet to restore OCTN2 levels prior to any carnitine interventions. Conversely, intestinal absorption increases in carnitine deficiency states.
Absorption speeds are relatively the same amongst Carnitine compounds, although L-Carnitine L-tartrate has been shown once to be slightly faster absorbed and peak in the blood faster than Acetyl-L-carnitine and L-Carnitine.
Intradermal delivery of L-Carnitine 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.
Absorbed moderately well relative to many supplements, although not perfect. Greater absorption from foods, but the overall dose from foods is low.
Studies in which a dose of 500mg Acetyl-L-Carnitine is given orally result in peak serum levels (Tmax) somewhere around 3.1-3.4 hours. Another study with 2g Carnitine, but in three forms (L-Carnitine, Acetyl-L-Carnitine, Propionyl-L-Carnitine) showed L-Carnitine with the highest Cmax (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. Another study looking at L-Carnitine at the same dose (2g) noted the same Cmax value of 84.7 ± 25.2 µmol/L. 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.
The half-life of 500mg ALCAR is 4.2 hours and has high individual variability. One study noted the half-life was approximately 60+/-15 minutes after ingestion of 2g L-Carnitine in liquid form.
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 but does not affect basal L-carnitine flux..
Carnitine, in the serum, 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.
L-Carnitine is excreted via the kidneys via tubular resorption as the metabolite trimethylamine, which has excretion rates correlated with plasma levels. Acutely, renal resorption of carnitine and carnitine metabolites is able to regulate serum carnitine levels within the aforementioned range.
Carnitine can also be excreted fecally via the precurosor turned metabolite y-butryobetaine. 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.
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.
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'. 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.
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.
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.
Basically, in the mitochondria L-Carnitine 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.
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) and alleviates the decline in mitochondrial count seen during aging.
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. In regards to the mitochondria, aging is associated with a decreased ability for oxidative phosphorylation.
Acetyl-L-Carnitine supplementation can attenuate the decline in mitochondrial membrane potential and cardiolipin (a membrane constituent) associated with age (and overnutrition). 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. It has been hypothesized to be a junction point of Acetyl-L-Carnitine and aging, as ALCAR has mechanisms to restore cardiolipin levels. However, it does not appear that cardiolipin levels are significantly decreased with aging, at least in regards to the heart.
At least one cognitive benefit seen from Acetyl-L-Carnitine supplementation (after rat feeding) was associated with improvements in the cristae of the mitochondria, a structural basis. When looking into the proteins related to cristae that are affected by ALCAR supplementation in the rat liver, 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). ALCAR did not affect PDCE2, which increased with aging. Identification of some of these age-related changes have been replicated without ALCAR.
The former study's benefits were also associated in part to reduced oxidation of RNA, however. 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.
As mentioned before, Acetyl-L-Carnitine supplementation is associated with an attenuated decline in mitochondrial count during aging.
Mechanistically, ALCAR supplementation has the ability to reduce 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 pro-longevity effect may be a more 'life to years' effect rather than a 'years to life' one, however.
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 timethylamine 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.
It is unsure how much concern should be paid to this information due to the high dose used, but it seems unlikely that carnitine could cause artherosclerosis in supplemental doses
ALCAR in conjunction with ALA can potentially reduce hypertension in via their combined anti-oxidant and pro-energetic effects as well as insulin resistance and glucose tolerance in those with compromised cardiac health 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.
May benefit blood pressure in unhealthy persons (metabolic syndrome, high blood pressure). 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 those 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 and improve quality of life. 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. In persons with peripheral arterial diseases, PLC supplementation can increase strength and exercise performance although exercise itself can also be seen as therapeutic.
Quite promising for periphery artery disease and intermittent claudication
During aging, defects in oxidative phosphorylation occur exclusively in Interfibrillar mitochondria, located between myofibrils. 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. Enzymatic activity of complexes III (through cytochrome C binding) and IV also appear to be decreased during cardiac aging.
It appears these damages may be secondary to cardiac Ischemia. Ischemia causes damage to the Electron Transport Chain after 10-20 minutes via reducing activity of complex I and reducing phosphorylation at complex V and adenine dinucleotide translocase. Complex III and IV are hindered at longer periods of Ischemia. It appears that the general process of Ischemia hits elderly persons harder than youth despite some level of damage at both ages.
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. 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.
Another possible mechanism is increasing levels of CPT1 in the myocardium, without affecting overall carnitine levels. 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 which are thought to be due to less CPT1 activity.
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.
One meta-analysis assessing the role of L-Carnitine in secondary prevention of cardiovascular disease assessing 13 trials conducted on the topic in persons who sufferred a myocardial infarction 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). The authors hypothesized that Carnitine would be effective in persons with acute myocardial infarction and stable angina.
Appears to confer protective effects to persons 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. 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. 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 or in obese women with 2g of L-Carnitine daily and aerobic exercise.
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.
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, Glycogen depletion rates are also not affected. After exercise a slight trend towards fat oxidation (as assessed by respiratory quotient) has been noted.
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. 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. 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.
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.
In sum, 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 a hindered fat burning potential.
ALCAR, in general, has a variety of effects in the brain including; synthesizing lipids, altering and stabilizing membrane composition, modulating genes and proteins, improving mitochondrial function, increasing antioxidant activity, and enhancing Cholinergic neurotransmission.
Acetyl-L-Carnitine may also increase glucose uptake in neurons.
In lab animals, ALCAR supplementation has been shown to improve markers of learning in older mice 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. ALCAR is currently under investigation for being of potential use in combatting Alzhemier's Disease and Dementia and older mice after ischemia. 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.
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 and a year. General cognitive decline (not Alzheimer's) shows similar benefit in aged individuals at 1-2g daily. 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. 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, 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. It is still, however, touted as being a viable conjunct treatment with other neurological protective compounds.
Appears to be a good therapy for cognitive decline, although its usage in otherwise healthy people has not been well studied
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. Administration of Acetyl-L-Carnitine at 2mg/mL in the water of rats reduced oxidative damage and neuronal loss from alcohol.
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.
Acetyl-L-Carnitine can also induce Heme-Oxygenase 1 in the brain in a dose and time dependent manner, this was accompanied by an increase in Heat Shock Protein 60 content and NRF2 expression.
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. 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. In fact, carnitine repletion therapy (for deficiencies) tends to warn about possible hypoglycemia from glucose disposal.
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. 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.
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.
The mechanisms by which it increases muscular uptake of glucose is via stimulation of AMPK-mediated glucose uptake Carnitine supplementation can also downregulate TNF-a's suppressive effects on glucose uptake.
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. L-Carnitine could also simply shuttle these acyl groups into the mitochondria to be burnt during beta-oxidation (fat burning). 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.
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 persons 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. This usually occurs during hyperinsulinemia (700pM or more) which occurs after food, as baseline insulin secretion does not influence carnitine deposition.
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.
L-carnitine has been actively explored in humans as a way to combat cachexia (muscle wasting) and fatigue associated with cancer . A one week phase I/II open label study of L-carnitine supplementation showed improvements in fatigue, mood, and sleep . Furthermore, a randomized phase III clinical trial with patients with advanced cancer showed significant improvements in fatigue , however a followup phase III study showed that L-carnitine supplementation alone had an insignificant effect on fatigue .
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 .
Not really a cancer preventative agent, but is being explored for its inclusion into chemotherapy to assist in side-effects, cachexia, and appetite. Possibly related to carnitine deficiencies that occur in some cancer metabolisms.
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. 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 and still does not increase test in a population of men going through andropause (male equivalent of menopause) despite controlling other symptoms. 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.
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 test 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.
Supplementing with L-carnitine (in conjunct with Caffeine and choline) increases VO2 max in rats, although the doses used quite high (at 5g ALCAR and 11.5g choline per kg diet) and promotes carnitine influx into tissues.
There is not a consensus that moderate to high doses of L-Carnitine improve athletic performance although the mechanisms by which athletic performance can be improved exist with carnitine supplementation.
In looking at human interventions, L-Carnitine at 15g can promote aerobic endurance whereas smaller doses (2g) are ineffective. 3g of Glycine-Propionyl-L-Carnitine was also seen as ineffective. 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.
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. 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. 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.
Mixed results. Doesn't seem to reliably increase aerboic exercise in 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 needs more studies.
Exercise Damage is a term used to refer to various biomarkers that are increased during exercise that are indicative of damaged tissues or metabolic processes, and in some cases may cause fatigue or acute failure of muscle contraction. In general, L-Carnitine supplementation appears to be quite effective at either reducing the levels of or attenuating the increase of these products.
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. This has been replicated with just L-Carnitine as well. A possible mechanism is enhancing oxygenation of muscle and thus recovery from hypoxic (anaerobic) exercise.
Carnitine supplementation, as either Acetyl-L-Carnitine or GPLC, has been shown to increase Nitric Oxide levels or plasma nitrate/nitrite 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. 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.
Seems to reduce markers of muscle damage after anaerboic exercise, possibly through enhancing oxygenation of tissue when oxygen is lacking. This mechanism might also explain the greater work volume seen in one study.
Carnitine, specifically Acetyl-L-Carnitine (ALCAR), is being investigated for chronic fatigue syndrome as a biomarker of fatigue is alterations in the levels and distribution of ALCAR in the brain at rest; specifically the pre-frontal cortex. This tends to be accompanied by a reduced uptake of ALCAR into the brain, which may precede the reduced neural levels of ALCAR.
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.
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). 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.
It has been shown to decrease fatigue in a human population of hepatic encepalopathy, secondary to reducing ammonia levels which tend to induce fatigue, reduce quality of life, and hinder cognition. 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. 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. Carnitine deficiency is prevalent among some forms of Cancer and reversing this deficiency can theoretically reverse fatigue. That being said, not all studies come back positive. Doses tend to be around 2-3g daily of L-Carnitine or Acetyl-L-Carnitine.
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). It seemed to be effective at a concentration of 0.5uM and 5uM.
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. The mechanisms of interference include competing for intestinal absorption and reversing resorption by the kidneys. In fact, supplementation with D-Carnitine in isolation can reduce body stores by inhibiting dietary usage and induce a Carnitine deficiency. Due to these reasons, the L-Carnitine molecule is highly preferred.
Acetyl-L-Carnitine, also known as ALCAR, is a carnitine molecule bound to an Acetyl-CoA moiety. For all intents and purposes it can be treated as two molecules.
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.
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. 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.
The initial stages of metabolism are undergone by the enzyme Carnitine acetyltransferase, the same enzyme that mediates the breakdown of ALCAR to L-carnitine.
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. GPLC has also been used to increase Nitric Oxide production in sedentary men and athletes at doses of 3-4.5g daily.
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. It is used quite frequently in athletic studies due to the quicker influx of L-Carnitine coinciding with activity when taken before.
Although an oral dose of ALCAR and ALA is associated with decreased mitochondrial oxidation ALCAR alone is associated with more oxidation secondary to increased metabolic activity. This associated is dose dependent, as low doses in isolation may not increase oxidation while higher dosages do.
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. However, at least one study noted that the effects of carnitine were not furthered by this increased deposition.
Choline and L-Carnitine ingestion also seem to be able to reduce fat mass in rats and humans 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%. One rat study, however, noted augmentation in adult rats (+18%) but inhibition in suckling rats. 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. Carnitine is able to do this as well, and the combination is synergistic rather than additive in hepatocytes. 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.
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.
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. 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.
The mechanism of anti-oxidation may be stabilization (prolonging the efficacy of) an intrinsic anti-oxidant enzyme known as Superoxide Dismutase.
Alcohol appears to be able to reduce glucose uptake into the brain via reducing the activity of the GLUT1 transport, 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. Acetyl-L-Carnitine may alleviate these effects. 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. Acetyl-L-Carnitine also reduced the alcohol-induced increase in Blood Brain Barrier permeability.
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.
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.
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