Acetyl-L-Carnitine
Acetyl-L-carnitine acts as an acyl moiety carrier, facilitating the translocation of long-chain fatty acids across the mitochondrial membrane for subsequent β-oxidation. It is instrumental in the generation of adenosine triphosphate (ATP) via oxidative phosphorylation and can serve as a substrate for acetylcholine synthesis, a neurotransmitter essential for synaptic plasticity, particularly in the hippocampal and cortical neurons.
Literature Review
Cognitive Improvement in the Elderly: Clinical studies suggest that a daily dose of 1500-2000 mg of acetyl-L-carnitine for a three-month period appears to enhance cognitive function and memory in older individuals experiencing age-related cognitive decline.[i],[ii],[iii]
Fatigue Reduction: A specific clinical trial reveals that elderly patients taking 2 grams of acetyl-L-carnitine twice a day for 180 days experience a significant decrease in both physical and mental fatigue—by 52% and 43% respectively. In comparison, those taking a placebo only see a 4% and 8% reduction. Additionally, post-exercise fatigue is lowered by 51% in those on acetyl-L-carnitine, versus a mere 4% in the placebo group.[iv]
Mood Regulation in Elderly: Multiple clinical trials have been carried out to explore the effects of acetyl-L-carnitine on older adults suffering from disorders related to mood regulation.[v],[vi],[vii]
A European meta-analysis comprising these and other related studies indicates that a daily intake of 1-4 grams of acetyl-L-carnitine for 3-24 weeks moderately alleviates symptoms of decreased mood, compared to a placebo. The compound appears to be as effective as standard therapies, especially when administered at higher doses. The duration of the treatment and the initial severity of symptoms do not seem to impact the outcomes.[viii]
Mechanism of Action
General: Acetyl-L-carnitine is a naturally occurring compound in the human body. Within cells, a "carnitine pool" exists, comprised of L-carnitine and various acetyl-carnitine esters. These compounds can be quickly transformed and transported to where they're needed by specific enzymes and membrane transporters.
As the primary carnitine ester, Acetyl-L-carnitine is converted into L-carnitine through enzymatic processes by carnitine acetyltransferase.[ix],[x] Carnitine is obtained from dietary sources like red meat and dairy, as well as synthesized from amino acids like lysine and methionine. The kidneys help maintain stable carnitine levels.32
Carnitines are vital for lipid metabolism and energy creation. They facilitate the movement of long-chain fatty acids into mitochondria for energy production.[xi],[xii],[xiii],[xiv],[xv],[xvi] Acetyl-L-carnitine also removes harmful acids and fatty acid fragments from cells.[xvii]
A deficiency in carnitine, often due to genetic metabolic disorders, frequently manifests as progressive heart muscle disease and muscle weakness, sometimes accompanied by hypoglycemia during fasting.34
Acetyl-L-carnitine may act as a neuromodulator by stimulating the synthesis of membrane phospholipids, stabilizing cell membranes.37,38 It also has various other roles including protein and gene expression, nerve growth factor production, and interaction with glutamate receptors.37,38. It also has a direct and indirect effect on the N-methyl-D-aspartate (NMDA) glutamate receptors via activation of cholinergic receptors.38
Age-Related Cognitive Decline Morbidity: Acetyl-L-carnitine shares structural similarities with acetylcholine and serves as a precursor to acetyl coenzyme A (acetyl-CoA).31,38 It has been studied for its potential in morbidities related to age-related cognitive decline due to its ability to promote acetylcholine release and enhance related enzyme activity in conditions in which there is substantial cholinergic neuronal loss and acetylcholine depletion.[xviii],[xix] It may also reduce oxidative stress and damage in the brain, more effectively than L-carnitine.[xx]
Improvement of Insulin Sensitivity: Carnitine levels are lower in people with complications of dysregulated glucose uptake and utilization (i.e. diabetes).[xxi] Early studies suggest that acetyl-L-carnitine could improve glucose metabolism by affecting the expression of certain metabolic enzymes.[xxii]
Antineuropathy effects: In nerve pain and degradation related to insulin resistance and systemic inflammation, there is damage to sensory neuronal membranes. This causes an increase in sodium channels, which increases spontaneous neuronal firing. Acetyl-L-carnitine is thought to reduce or slow down nerve degeneration, possibly aiding in nerve repair.[xxiii]
References
[i]Mayeux R, Sano M. Treatment of Alzheimer's Disease. N Engl J Med 1999;341:1670-9.
[ii]Salvioli G, Neri M. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res 1994;20:169-76.
[iii]Passeri M, Cucinotta D, Bonati PA, et al. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res 1990;10:75-9.
[iv]Malaguarnera, M., Gargante, M. P., Cristaldi, E., Colonna, V., Messano, M., Koverech, A., Neri, S., Vacante, M., Cammalleri, L., and Motta, M. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch.Gerontol.Geriatr. 2008;46(2):181-190
[v]Bella R, Biondi R, Raffaele R, Pennisi G. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 1990;10:355-60.
[vi]Garzya G, Corallo D, Fiore A, et al. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res 1990;16:101-6.
[vii]Tempesta E, Casella L, Pirrongelli C, et al. L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo. Drugs Exp Clin Res 1987;13:417-23.
[viii]Veronese N, Stubbs B, Solmi M, Ajnakina O, Carvalho AF, Maggi S. Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis. Psychosom Med. 2018;80(2):154-9.
[ix]Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol Psychiatry 2000;5:616-32.
[x]Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 2004;1033:30-41.
[xi]Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS 2004;18:1549-60.
[xii]Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004;1033:42-51.
[xiii]Evans AM, Fornasini G. Pharmacokinetics of L-carnitine. Clin Pharmacokinet 2003;42:941-67.
[xiv]Sima AAF, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: An analysis of two randomized, placebo-controlled trials. Diabetes Care 2005;28:89-94.
[xv]Goodison G, Overeem K, de Monte V, Siskind D. Mania associated with self-prescribed acetyl-l-carnitine in a man with bipolar I disorder. Australas Psychiatry. 2017;25(1):13-4.
[xvi]Bruno A, Pandolfo G, Crucitti M, Lorusso S, Zoccali RA, Muscatello MR. Acetyl-L-Carnitine Augmentation of Clo****** in Partial-Responder Schizophrenia: A 12-Week, Open-Label Uncontrolled Preliminary Study. Clin Neuropharmacol. 2016;39(6):277-80.
[xvii]Rolim LC, da Silva EM, Flumignan RL, Abreu MM, Dib SA. Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy. Cochrane Database Syst Rev 2019 Jun 15;6:CD011265.
[xviii]Mayeux R, Sano M. Treatment of Alzheimer's Disease. N Engl J Med 1999;341:1670-9.
[xix]Thal LJ, Carta A, Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's Disease. Neurology 1996;47:705-11.
[xx]Liu J, Head E, Kuratsune H, et al. Comparison of the effects of L-carnitine and acetyl-L-carnitine on carnitine levels, ambulatory activity, and oxidative stress biomarkers in the brain of old rats. Ann N Y Acad Sci 2004;1033:117-31.
[xxi]Tamamogullari N, Silig Y, Icagasioglu S, Atalay A. Carnitine deficiency in diabetes mellitus complications. J Diabetes Complications 1999;13:251-3.
[xxii]Mingrone G. Carnitine in type 2 diabetes. Ann N Y Acad Sci 2004;1033:99-107.
[xxiii]Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002;288:2579-88.
