Cholinergic Supplementations: Which One is Superior for Cognitive Function?

Last Updated on 1 day by Liam Lopez

The human body can benefit from many vitamins, minerals, proteins, carbohydrates, fats, and oils. However, certain variations of each are detrimental to the organs, muscle tissues, nervous system, and general health. Simultaneously, there are healthier variations that some have considered avoiding due to having words associated with their negative counterparts. Some of these components are vital to human health, and without them, numerous bodily and neurological functions can decrease performance and increase the complications for the development of inhibiting disorders. Some examples are lung disease, cardiovascular disease, Alzheimer’s, dementia, mood disorders, anxiety disorders, delusional and psychotic disorders such as schizophrenia, and obsessive-compulsive complications. One mineral that is vital to human development and cognitive function is choline. Choline is a nutrient needed for proper or optimal functioning of the liver and the muscular and nervous systems. It contributes to other systems (such as modulating gene expression, in which genetic information is used for protein and cell development, cell membrane signaling, lipid transportation, metabolism, and vital for early brain development (during pregnancy and childhood growth).

Choline has two main contributions:

1. The main constituent that helps develop cell and organelle membranes. These are barriers that protect the internal cells from the environment. If these are degraded or damaged, the inner cell becomes vulnerable.
2. It is a precursor to acetylcholine, phosphatidylcholine, sphingomyelin, and betaine.
   • Acetylcholine is known as the higher-cognitive neurotransmitter or learning neurotransmitter. It is a neurotransmitter and neuromodulation (a component that controls numerous specialized neurons or a neuronal group), responsible for countless higher-cognitive functionalities, such as arousal (stimulated by a source), attention and concentration, learning and memory, and the neuromuscular junction (synapses between motor neuron axon terminal and the section of a muscle fiber where receptors (such as acetylcholine) are sent to trigger movement. Essentially, this is the postal service building where the acetylcholine is sent to execute a specific action, such as voluntary muscular control. Your physical exercises will increase, regardless of the choline supplement you are taking. Another point is it interacts with the monoaminergic neurotransmitter systems, commonly dopamine, serotonin, and noradrenaline.
   • Phosphatidylcholine is a crucial phospholipid (a plasma membrane constituent comprising the cell’s outermost layer, mainly involved in cellular membrane development and reconstruction). It is also essential for dendritic membranes.
   • Sphingomyelin is a sphingolipid crucial for plasma membranes and commonly distributed across the central nervous system.
   • Betaine is a substance metabolized from choline. It is essential for maintaining intracellular osmotic pressure and protecting cells, proteins, and enzymes from osmotic stress; one method is to have cells control water surface tension. It can help reduce inflammation or contribute to the healing process of liver disorders, commonly by preserving gut integrity and adipose function (the academic term for fat). Furthermore, It donates its methyl group to homocysteine (a toxic metabolite due to promoting oxidative stress), converting it into methionine (essential for metabolism and DNA and gene functionalities). This reaction is catalyzed by betaine-homocysteine methyltransferase (BHMT).

Fat—and water-soluble choline compounds and free choline (the molecule itself) exist in ways you can consume choline. When you consume these solubles, pancreatic and mucosal enzymes detach the choline from the compounds, with the cholinergic components absorbed into the small intestine, they are either stored, transported to make cell membranes, or distributed to tissues and the nervous system to be further metabolized.

The Parasympathetic nervous system and Acetylcholine

We know acetylcholine’s general and specific functions, but how does the body use it? It is commonly used through the sympathetic, central, and parasympathetic nervous systems.

Both of these systems release acetylcholine, often in conjunction with other neurotransmitters. But, acetylcholine is frequently the dominant neurotransmitter for the parasympathetic nervous system, where you have low blood pressure, a slow heart rate, and a state of physical and mental relaxation. For the sympathetic nervous system, the preganglionic neurons (neurons that connect to the spinal cord and brain, then send signals to the ganglia) axons release acetylcholine on the postganglionic neurons within the ganglia to release norepinephrine.

If your diet does not permit choline-dense foods or cannot reach your daily requirement, what other means are required to meet daily requirements for choline? This is where supplementation comes in. Three prevailing methods for acquiring choline are citicoline, alpha-gpc, and choline biartrate.

Most of the general public is under a choline deficiency, often due to a lack of awareness of this essential nutrient, diet choices, and high costs in certain regions. When taken in supplement form, it is considered a ‘nootropic‘ or “brain-enhancement drug.” The questions that remain are:

1. What is the safest and most beneficial for your health?
2. Am I required to take the supplement daily?

These choline supplements are ranked based on their functionalities (what they do to the body), risk management, and costs. They are provided so readers have a straightforward approach.

Citicoline: More Than a Cholinergic Supplement

Citicoline (CDP choline or cytidine diphosphate choline) is a cholinergic supplement that combines choline and cytidine. We know what choline does, but what does cytidine do? Cytidine is a component of RNA and a nucleotide. Before continuing, we must understand that cytidine is a pyrimidine (an organic compound characterized as a ring structure composed of four carbon and two nitrogen atoms). These derivatives, prodrugs or precursors, are different in numerous Earth-based species. For example, it is cytidine in rats, and in humans, it is uridine. Uridine is a compound converted from cytidine through the enzyme cytidine deaminase. Uridine is a nucleoside that can be considered a “nootropic.” It is essentially an RNA nucleotide that contributes to the Kennedy pathway (segmentations of the CDP-ethanolamine pathway for phosphatidylethanolamine synthesis and the CDP-choline pathway for phosphatidylcholine synthesis). Additionally, it can increase brain phosphatide levels, stimulate synaptic proteins by an agonist for the P2Y2 receptors, and increase neuronal growth, neurite-bearing cells, neurite extension, and the combined length of the aforementioned neurites per cell. Here, we have a multi-purpose compound that can assist in RNA and gene expression, brain development, cognitive function, and several bodily functions, often in conjunction with choline.

Furthermore, it is essential for glycogen and bio-membrane synthesis and is a nervous system regulator (including thermoregulation) through its metabolite, β-alanine. It also causes enhanced slow brain waves, which are often seen in deep relaxation or sleep. However, this effect can vary between species (due to rats promoting sleep while humans are induced a fever). Further into this statement, some people supplementing with citicoline reported feeling more sleepy. Uridine is a neuromodulator, and its effects affect the dopaminergic and GABA neurotransmitter systems. It can either enhance or inhibit its release in certain situations. For example, uridine can promote dopamine to improve your motivation, happiness, joyful attitude, and composure, but stops it to regulate the release, such as morphine (morphine is a pain-killer that can increase pain tolerance, but the human body has endorphins and dopamine that do that for us). GABA is often the cause of neurotransmitter inhibition; depending on the situation, it can have beneficial yet unwanted effects. Uridine interferes with this dopaminergic system by acting as an agonist at GABA receptors.

Alpha-GPC: A Daily Reacher to Your Daily Value

Alpha-GPC (alpha-glycerophosphocholine, or choline alphoscerate) is a choline-containing phospholipid. It is the combination of choline and glycerol-1-phosphate (supports cellular membranes).

It is a beneficial cholinergic supplement to help you reach your daily values. One gram (containing 41 % choline by weight) is enough for your daily value. Like all choline supplements, it can help boost acetylcholine production and availability. Alpha-GPC can help increase acetylcholine levels and enhance neuroblast formation (a neuroblast is a postmitotic cell that does not divide after a certain period; when this occurs, it will develop into a neuron), and thereby reduce neuron death and cognitive impairment when brain damage has occurred. We know acetylcholine can modulate or affect numerous neurotransmitters, especially the monoaminergic systems. For alpha-gpc, this is done by increasing cerebral metabolism from synthesizing structural phospholipids in neuronal membranes. Dopamine, serotonin, and noradrenaline were boosted and continued to level after continuous administrations. However, there are concerns surrounding the long-term supplementation of alpha-glycerophosphocholine. Though it has numerous acute and long-term benefits, some can outweigh them in certain situations. For example, it has cytoprotective effects on cardiac myocytes when oxidative stress is induced, but it causes cell death if the compound remains nearby.

Furthermore, the main concern is the increased risk of a stroke, with a 40 – 50% higher chance. This is common for most foods, with the majority providing minor-to-moderate increases, including choline supplements. Choline contains trimethylamine moiety, a precursor to TMAO, and is metabolized by gut microbiota, which is the concern behind the risk of stroke and cardiovascular complications. Trimethylamine N-oxide has some contribution to the increased risk but is not entirely responsible for the stroke risk. A common argument against TMAO not being a cause of these disorders is that these precursors for TMAO are everywhere. This is true, as described earlier, but other compounds exist in the liquids and foods you eat.

Concerning Trimethylamine N-oxide

If your diet is Mediterranean, consuming certain foods can increase your TMAO. Still, some meals and fluids are potent anti-oxidative, antimicrobial, anti-depressant, and anxiolytic, along with numerous minerals and vitamins that outweigh and overcome the adverse effects of unhealthy fats, proteins, and compounds, including TMAO—granting the illusion that TMAO is non-harmful. So, what is the core argument here? The argument is that “healthy foods we eat raise TMAO levels, yet I am healthy; thereby, TMAO does not promote cardiovascular disease, strokes, neurodegeneration, and impair bodily functionalities.” This is a somewhat commonplace error. Does TMAO have a connection to these increased complications or pre-existing disorders and diseases? It is feasible, but is it safe because I don’t experience the proposed negative consequences of eating foods promoting TMAO levels even though the same foods and liquids I am eating counteract these effects? No, as there are more contributors to these illnesses and compromises of the body. As explained in one of the core messages of Sciucation, there are always exceptions. A short paragraph of the adverse effects proposed for TMAO is described here.

Timethylamine-N-oxide can have some part in impairing insulin responsiveness, resulting in further developing diabetes, promoting oxidative stress and free radicals by enhancing reactive oxygen species (ROS) production, reducing antioxidant activity, triggering neuroinflammation, disrupting the blood-brain barrier by decreasing the expression of zonula occludens-1 (ZO-1) and occludin in the hippocampus and impacting your cognitive function if this continues. There are reductions to pericyte marker platelet-derived growth factor receptor beta (PDGFRβ) for the blood-brain-barrier disruption.

If you desire to eliminate TMAO, it can be an enjoyable process. The foods and fluids you consume can increase TMAO levels, but they also have benefits that can help heal the body and brain. Furthermore, you can perform physical exercises to decrease TMAO levels.

Choline Bitartrate: The Latter of the Bunch

Choline Bitartrate is a choline supplement made from choline and tartaric acid. It is considered more affordable and easy to manufacture. However, crossing the blood-brain barrier is complex, often compared to phosphatidylcholine, so you will not acquire the “nootropic” benefits it provides if you have a choline deficiency. Furthermore, choline bitartrate has various impacts on the individual. For example, some experience enhancements in working memory, learning, and muscular control, while some reported little to no difference. Regardless, you are technically meeting your daily intake due to having more choline weight per gram (frequently around 40%). Since the bioavailability (in the context of the brain-blood barrier and receptors across the entire body: (1) muscarinic acetylcholine receptors and (2) nicotinic acetylcholine receptor) is not on the same magnitude as citicoline and alpha-gpc, you are welcomed to gain a portion of your choline from your diet or use the previous mentioned cholinergic supplements.

Conclusions

We conclude by returning to the first two questions:

1. What is the safest and most beneficial for your health?
2. Am I required to take the supplement daily?

After assessing the top three cholinergic compounds, we can conclude that citicoline is a better alternative to your cognitive function (and mental health). Citicoline is a compound composed of choline and citicoline (converted into uridine) that can help promote neurotransmitter acetylcholine synthesis for higher-cognitive functionalities and neuro-muscular control; you are also getting the benefits from uridine for RNA and gene expression repairment and development, increase brain phosphatide levels, stimulate synaptic proteins (for increasing synapse development) by acting as an agonist for the P2Y2 receptors, increase neuronal growth, nervous system regulation, and promote or inhibit the release of dopamine and GABA. The answer to the second question is no, but that is your choice. You can buy citicoline from numerous brands. One company I buy from is Nootropics Depot; they do not sponsor me.

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