Acetyl-L-Carnitine:The King of Carnitines

by A.S. Gissen

Acetyl-L-Carnitine (ALC) is the acetyl ester of carnitine, the carrier of fatty acids across mitochondrial membranes. Like carnitine, ALC is naturally produced in the body and found in small amounts in some foods.

The reversible formation of ALC in the body modulates cellular concentrations of free coenzyme A and acetyl-coenzyme A, compounds integrally involved in numerous cellular functions including energy production. By exchanging across sub-cellular membranes, ALC serves as a pool of acetyl groups to regenerate acetyl-CoA from free coenzyme A. While this natural role for ALC in cellular metabolism has been well established for decades, research in recent years has hoisted ALC from its somewhat mundane role in energy production to nutritional cognitive enhancer and neuroprotective agent extraordinaire. Indeed, taken in its entirety, ALC has become one of the premiere “anti-aging” compounds under scientific investigation, especially in relation to brain and nervous system deterioration.

ALC is found in various concentrations in the brain, and its levels are significantly reduced with aging.(1) In numerous studies in animal models, ALC administration has been shown to have the remarkable ability of improving not only cognitive changes, but also morphological (structural) and neurochemical changes. Initially, these effects were thought to stem from ALC’s ability to donate its acetyl group to help form acetylcholine, or its ability to mimic acetylcholine, a neurotransmitter known to have an important role in memory and related cognitive functions.

In fact, it is now known that ALC has varied effects on cholinergic activity, including promoting the release(2) and synthesis(3) of acetylcholine. Additionally, ALC promotes high affinity uptake of choline, which declines significantly with age.(4) While these cholinergic effects were first described almost a quarter of a century ago,(5) it now appears that this is only the tip of the ALC iceberg. In recent years research on the neurological and other effects of ALC has exploded, primarily due to pharmaceutical interest in this fascinating compound. This large volume of research has expanded ALC from acetylcholine mimic to a safe and naturally occurring compound with varied effects on numerous age-related degenerative changes in the brain.

The discovery that ALC has effects on brain systems other than the cholinergic system complicated the scientific picture of ALC. This is because it was generally believed that ALC functioned simply as an enhancer of cholinergic activity by promoting the production, or mimicking the effect, of acetylcholine. Before we examine these varied effects, however, let's examine what is now known about ALC’s effects on the cholinergic system. The cholinergic system has been extensively researched because of its central role in memory, as well as the evidence that cholinergic dysfunction plays a large role in age-related memory loss. This is most evident in Alzheimer’s disease, which effects primarily cholinergic function. As mentioned earlier, ALC effects both acetylcholine synthesis and release. Additionally, long-term ALC treatment has shown the ability to restore the decrease in cholinergic receptors in some brain areas. One study found that the functioning of the cholinergic synapse was disturbed due to altered properties of the neuronal membrane, resulting in the functional impairment of cholinergic receptors. Old rats treated with ALC were found to have improved acetylcholine release due to a preservation of the neuronal membrane structure and the functioning of the receptors embedded within the membrane.(6) Indeed, these varied effects have shown that long-term ALC treatment reduces the significant age-related difference in receptor-mediated acetylcholine release. This has not gone unnoticed, and ALC has been studied in Alzheimer’s disease patients with promising results.

While ALC’s cholinergic-enhancing properties are exciting, it now appears that ALC possesses broader neuroprotective and neuroenhancing properties than previously thought. For instance, it is now known that ALC has effects on the dopaminergic system.(7) The decline of this neurotransmission system is most evident in Parkinson’s disease patients. ALC has shown the ability to improve age-related changes of dopamine receptors, including improved release and binding of dopamine. Additionally, ALC can prevent dopaminergic neuron death by the neurotoxin MPTP.(8) MPTP causes neurological symptoms similar to Parkinson’s disease by selectively killing dopaminergic neurons. Thus, it appears that ALC can have numerous beneficial effects on dopaminergic neurons.

One of the most important receptor systems involved with cognitive function and memory is the NMDA receptor system. NMDA (N-Methyl-D-Aspartic acid) receptors are widely distributed in the brain, and their effects are mediated by excitatory amino acids like glutamate. These receptors are unique because receptor function is mediated not only by the interaction between receptor and excitatory amino acid, but is dependent on the membrane potential. Thus, activation of these receptors requires additional synaptic inputs. While this may sound confusing, the point is that NMDA receptors have a “conditional” nature to their activation, which is highly unusual. This underlies the central role that NMDA receptors are now believed to play in the synaptic plasticity associated with learning and memory. Indeed, a rapidly growing body of evidence suggests that excitatory amino acids, through their interaction with NMDA receptors, are involved many aspects of neuronal activity. It has been established that the density of NMDA receptors declines with age and that treatment with ALC restores to a significant degree these receptor numbers.(9) In fact, even a single dose of ALC can significantly increase the number of available NMDA receptors.

One of the most important, and often overlooked, receptor system is that of glucocorticoids. The hippocampus in the brain is the site of negative feedback between the pituitary and adrenal gland, and this helps to regulate the production of glucocorticoids by the adrenals. The number of glucocorticoid receptors in the hippocampus declines significantly with age,(10) and this is thought to result in perturbations in the hypothalamus-pituitary-adrenal (HPA) axis. ALC treatment has been shown to prevent this age-related decline in receptor number.(11) Because these receptors are central to neuroendocrine aging, and their decrease is considered a consistent marker for aging, it appears that ALC may have substantial potential for helping to slow down neuroendocrine aging.

One of the most exciting areas of brain research has been into the functions of Nerve Growth Factor (NGF). NGF mediates much of its effects through a receptor system (NGF receptor system). Unfortunately, aging is associated with a significant drop in the number of NGF receptors in certain brain regions, as well as a decrease in the amount of NGF produced. ALC has shown the ability to partially reverse both of these changes, and has even been shown to have independent stimulatory effects on neuronal survival and growth.(12) Because NGF is important for the growth and continued maintenance of neurons, the age-related decline in NGF function is thought to be directly involved in brain aging. The administration of NGF’s are under investigation for the treatment of brain injury and damage, and ALC’s ability to enhance NGF effects may have tremendous potential in many diseases and conditions affecting the brain and nervous system.

Taken as a whole, ALC represents a novel supplement with tremendous potential. Because it also increases tissue levels of carnitine, as well as providing many benefits not found with carnitine supplementation, ALC represents an alternative to carnitine with enhanced properties and benefits.

Most human studies examining ALC have utilized doses from 500-2500 milligrams daily in divided doses. Younger, healthy persons would probably want to take 500-1000 milligrams daily, while those with cognitive deficit due to aging or injury may wish to take 1500-2500 milligrams daily. While no serious side effects have been noted in animal or human studies, ALC may cause symptoms of over-stimulation or headache in some sensitive individuals. However, these symptoms are not common and are usually caused by beginning with a high dose. One last consideration is ALC’s stability. Unlike carnitine, it is recommended that ALC be kept refrigerated to ensure potency. Thus, while ALC can be shipped without refrigeration, manufacturers must be sure to refrigerate raw material and finished product during storage to prevent premature degradation of the product. Customers, to further protect their investment, should preferably refrigerate ALC after receipt.

ALC truly represents one of the most promising and well researched cognitive-enhancing compounds available today. The fact that its non-toxic, occurs naturally in the body, and positively affects so many different neurological functions makes its potential both exciting and amazing.

References:
1). F. Maccari, A. Arseni, P. Chiodi, et al, Exp Geront 1990; 25: 127-134.
2). A. Imperato, M.T. Ramacci, L. Angelucci, et al, Neurosci Lett 1989; 107: 251-255.
3). V. Dolezal and S. Tucek, J Neurochem 1981; 36: 1323-1330.
4). D. Curti, F. Dagani, M.R. Galmozzi, et al, Mech Ageing Dev 1989; 47: 39-45.
5). K. Blum, E. Seifter, J. Seifter, J Pharmacol Exp Ther 1971; 178: 331-338.
6). A. Impeerato, M.G. Scrocco, O. Ghirardi, et al, Annals of the NY Acad Sci 1991; 621: 90-97.
7). H. Sershen, L.G. Harsing, M. Banay-Schwartz, et al, J Neurosci Res 1991; 30: 555-559.
8). I. Bodis-Wollner, E. Chung, M.F. Ghilardi, et al, J Neural Transm Park Dis Diment Sci 1991; 3: 63-72.
9). L. Fiore and L. Rampello, Acta Neurol 1989; 11: 346-350.
10). R.M. Sapolsky, L.C. Krey, and B.S. McEwen, J Neurosci 1985; 5: 1222-1227.
11). F.R. Patacchioli, F. Amenta, M.T. Ramacci, et al, J Neurosci Res 1989; 23: 462-466.
12). G. Taglialetela, L. Angelucci, M.T. Ramacci, et al, Brain Res Dev Brain Res 1991; 59: 221-230.

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No information in this article should be taken as a recommendation. If you have any questions about the relationship between Acetyl-L-Carnitine and your health, seek the advice of a qualified physician.

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