Opti-Biologics

“Presenting Scientific Research for Optimization of Everyday Life"

Supplement Review #1: Acetyl-L-Carnitine (ALCAR)


August 05, 2022

Background

Acetyl-L-carnitine (ALCAR) is a commonly supplemented molecule amongst many gym goers and nootropic formulators. L-carnitine is a naturally occurring molecule synthesized by the liver and kidneys and found primarily in cells that use fatty acids as fuel, such as skeletal and cardiac muscle. The role of L-carnitine is to shuttle fatty acids into the mitochondria for use as fuel. In the cytosol, a carnitine molecule interacts with a fatty acyl-CoA and forms a fatty acyl-carnitine molecule. A fatty acyl-carnitine, unlike a fatty acyl-CoA, can cross the outer membrane and enter the mitochondria via the Carnitine palmitoyl transferase I (CPT1) transporter. The fatty acylcarnitine molecule must now cross the inner membrane of the mitochondria to be oxidized and used as fuel because it is a double-membrane organelle. Once the fatty acyl carnitine crosses the inner membrane via a similar transporter protein as CPT1, the fatty acylcarnitine is broken down into fatty acyl CoA and carnitine. Carnitine is then reused to shuttle more fatty acyl CoA molecules into the mitochondria, and the fatty acyl CoA is then oxidized via beta-oxidation.
(Lundsgaard et al., 2018)
Once inside the inner mitochondrial membrane, the acyl-CoA (long-chain) is broken down in a series of steps into acyl-CoA (short-chain). Once converted into a shorter chain, a four-step reaction converts acyl CoA into a molecule of acetyl CoA and acyl CoA minus the 2 carbons used for the acetyl CoA. This acetyl-CoA is then used to power the Kreb’s cycle, which produces NADH and FADH2 and very little ATP. The NADH and FADH2 molecules are used in the electron transport chain and eventually power ATP synthase, which is responsible for the majority of ATP production. In theory, if the cell can shuttle more fatty acids into the mitochondria, then more ATP can be produced, thus resulting in more cellular fuel and better performance.

(Xiong, 2018)
 
Findings from the literature
ALCAR is a modified L-carnitine molecule that can be readily absorbed by the body through oral ingestion. The acetyl ester addition allows the L-carnitine molecule to pass the blood-brain-barrier (BBB) and thus allows easier access for neuron contact. In addition to increasing fatty acid metabolism in the mitochondria, ALCAR has demonstrated anti-oxidant properties. Additionally, ALCAR has been demonstrated to be neuroprotective in the hippocampus and improve mitochondrial biogenesis, or the creation of new mitochondria. Other studies using an established Parkinson’s disease model in rats concluded that ALCAR protects dopaminergic neurons and improves motor coordination. Other studies have shown that ALCAR administration prevented the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of Parkinson’s-induced rats. A study dating back to 1991 found that ALCAR administration in aging rats reduced the decrease in taurine and increased the amount of dopamine when electrically stimulated. ALCAR has also been demonstrated to fully reverse age-related synaptic transmission delays and improve short-term synaptic plasticity in mice. In short, ALCAR has a significant amount of scientific research supporting its use in a clinical setting, such as in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases, but also in fighting depression and other neurological-related disorders.


Depression
The most commonly known and misconceived hypothesis of depression etiology is the "imbalance of chemicals." However, with the recent support of an umbrella review, this hypothesis has been shot down and other hypotheses have come to light. One of these hypotheses is centered around synaptic plasticity, suggesting that depression is caused in some part by lessened plasticity. A "plastic" neuron is just one that can change in response to a stimulus, while a "rigid" neuron may require a more intense signal to invoke a change, if at all. The neurons of a depressed individual may be more rigid, thus having a psychological effect on the individual's well-being. Interestingly, ALCAR has been shown to improve synaptic plasticity in multiple brain regions across multiple disease states, thus making its administration plausible for treating depression. A 2022 meta-analysis concluded that mitochondrial modulators exert a moderate antidepressant effect, which when considering this molecule is readily available over-the-counter, is extremely promising.


Brain Fog
While brain fog is not a diagnosable condition, many people experience it. To some people, it may be known as chronic fatigue, or it may be due to some underlying condition. In otherwise healthy individuals, brain fog can be present when one is hungry, tired, overworked, or overstimulated. This "brain fog" can be especially present after training with heavy weights, intense cardiovascular exercise, or a heavy carbohydrate meal. The goal of using various nootropics is to eliminate this brain fog, which can be caused by a myriad of things, one of which is acute neuroinflammation. There are various compounds on the market that reduce neuroinflammation and protect against neuronal apoptosis, one of the most effective being ALCAR. While animal studies have used doses such as 100 mg/kg, which equates to 7 grams in a 70 kg individual, a much more mild dose of around 50 mg/kg has demonstrated efficacy. Although not present in the scientific literature, but in personal experience, a more conservative dose of 1,000 to 3,000 mg has shown cognitive benefits in otherwise healthy individuals. While no significant changes occurred in bipolar patients given ALCAR and alpha-lipoic acid in combination, many animal models support the use of both drugs for their aid in fatty acid metabolism and protection against neuroinflammation.


Erectile Quality
A study conducted on nerve-sparing erectile dysfunction rats administered ALCAR as a treatment. ALCAR administration significantly improved fibrotic markers such as transforming growth factor-beta. ALCAR treatment also promoted the nitric oxide-cyclic guanosine monophosphate pathway, which plays a crucial role in smooth muscle relaxation and neuronal signaling. There are limited studies exploring the effects of ALCAR administration for the treatment of erectile dysfunction; thus, a need for future studies to support this initial hypothesis is needed to establish a solid conclusion.


Cognitive Enhancement
For those individuals who are looking to improve cognition, this section briefly dives into the use of ALCAR as a nootropic. Nootropics are drugs that elicit an acute positive change in cognition, thus making individuals more productive and possibly in a "flow state". While many nootropic formulations are poorly optimized and trendy, there is still a growing demand for information on the subject. Those looking to purchase nootropics should be advised that a majority of proprietary blends are poorly designed and poorly purified. Research on each ingredient should be conducted and trialed on oneself for true optimization of a nootropic stack. As for ALCAR, its neuroprotective and synaptic plasticity effects make it an ideal candidate as a nootropic. In my personal experience, a dose of 250 mg to 2,000 mg elicits a strong effect. Depending on the individual's sensitivity to dopaminergic compounds, the dose should be adjusted accordingly. An appropriate dose should be slightly stimulating, similar to a 300 mg oral administration of L-tyrosine. For those looking to use ALCAR for its numerous benefits yet seeking a harder dopamine hit, feel free to combine an appropriate amount of ALCAR with an appropriate amount of L-tyrosine (1000 mg). 

 Meet The Author


Hello everyone, 
My name is Joshua Giblin. I am a post-bachelor researcher/research technician at USC. My interests range from nutrition to nanomedicine and also practical science to improve everyday life. Through this blog, I aim to communicate practical scientific research and present it to curious individuals so that an educated decision can be made. Thank you for reading the blog and showing your support. 

 
 

Editors


A special thanks to the people involved behind the scenes. Without them, these informative and influential posts would not be what they are.


Anna Richardson
Undergraduate

Molly Giblin
High School Student
 
Literature cited
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  2. Brennan, B. P., Jensen, J. E., Hudson, J. I., Coit, C. E., Beaulieu, A., Pope, H. G., Renshaw, P. F., & Cohen, B. M. (2013). A Placebo-Controlled Trial of Acetyl-L-Carnitine and α-Lipoic Acid in the Treatment of Bipolar Depression. Journal of Clinical Psychopharmacology, 33(5), 627–635. https://doi.org/10.1097/JCP.0b013e31829a83f5
  3. Gao, Y.-N., Zhang, Y.-Q., Wang, H., Deng, Y.-L., & Li, N.-M. (2022). A New Player in Depression: MiRNAs as Modulators of Altered Synaptic Plasticity. International Journal of Molecular Sciences, 23(9), 4555. https://doi.org/10.3390/ijms23094555
  4. Liang, L., Chen, J., Xiao, L., Wang, Q., & Wang, G. (2022). Mitochondrial modulators in the treatment of bipolar depression: A systematic review and meta-analysis. Translational Psychiatry, 12(1), 1–7. https://doi.org/10.1038/s41398-021-01727-7
  5. Lundsgaard, A.-M., Fritzen, A. M., & Kiens, B. (2018). Molecular Regulation of Fatty Acid Oxidation in Skeletal Muscle during Aerobic Exercise. Trends in Endocrinology & Metabolism, 29(1), 18–30. https://doi.org/10.1016/j.tem.2017.10.011
  6. Sershen, H., Harsing Jr., L. G., Banay-Schwartz, M., Hashim, A., Ramacci, M. T., & Lajtha, A. (1991). Effect of acetyl-L-carnitine on the dopaminergic system in aging brain. Journal of Neuroscience Research, 30(3), 555–559. https://doi.org/10.1002/jnr.490300313
  7. Singh, M., Miura, P., & Renden, R. (2018). Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held. Neurobiology of Aging, 67, 108–119. https://doi.org/10.1016/j.neurobiolaging.2018.03.015
  8. Singh, S., Mishra, A., & Shukla, S. (2016). ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats. Molecular Neurobiology, 53(7), 4286–4301. https://doi.org/10.1007/s12035-015-9361-5
  9. Singh, S., Mishra, A., Srivastava, N., Shukla, R., & Shukla, S. (2018). Acetyl-l-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats. Molecular Neurobiology, 55(1), 583–602. https://doi.org/10.1007/s12035-016-0293-5
  10. Smeland, O. B., Meisingset, T. W., Borges, K., & Sonnewald, U. (2012). Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice. Neurochemistry International, 61(1), 100–107. https://doi.org/10.1016/j.neuint.2012.04.008
  11. Wang, J., Song, J., Song, G., Hu, P., Sun, T., Liu, K., Xu, W., Liu, J., & Ruan, Y. (2022). Acetyl-L-carnitine improves erectile function in bilateral cavernous nerve injury rats via promoting cavernous nerve regeneration. The Journal of Sexual Medicine, 19(5, Supplement 2), S159. https://doi.org/10.1016/j.jsxm.2022.03.364
  12. Xiong, J. (2018). Fatty Acid Oxidation in Cell Fate Determination. Trends in Biochemical Sciences, 43(11), 854–857. https://doi.org/10.1016/j.tibs.2018.04.006 

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