Why is Acetone Choline Supplement Better?

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In recent years, nootropics, also called smart drugs, have gained popularity among people looking to improve their mental performance.

Acetylcholine is a neurotransmitter, or brain chemical, that plays a role in many key aspects of brain function, such as memory, thinking, and learning.

While acetylcholine supplements don&#;t exist, supplements that may indirectly raise acetylcholine levels have become popular among people interested in nootropics as a way to enhance mental performance.

This article explores the benefits and side effects of acetylcholine supplements, and outlines the best types.

What is acetylcholine?

Acetylcholine is a molecule that functions as a neurotransmitter (chemical messenger) in your body. This means it relays messages from your brain to your body through nerve cells (1).

It&#;s produced from acetyl coenzyme A, which comes from the sugar molecule glucose, and choline, with the help of an enzyme called choline acetyltransferase (1).

It has many important functions in the body and plays a role in muscle movement, thinking, working memory, and many other brain functions (2, 3).

Conversely, low acetylcholine levels have been linked to learning and memory impairments, as well as brain disorders, such as dementia and Alzheimer&#;s disease (2, 4, 5).

Because acetylcholine plays a role in brain functions, supplements that increase acetylcholine levels have gained interest as nootropics, natural or synthetic substances that may improve your mental performance.

Acetylcholine can&#;t be taken as a dietary supplement. However, supplements that increase the release of acetylcholine, such as choline supplements, and those that inhibit the breakdown of acetylcholine may boost acetylcholine levels.

Summary

Acetylcholine is a neurotransmitter that plays a role in muscle movement, thinking, working memory, and other aspects of the brain. Low levels have been associated with memory impairment and brain disorders.

How to increase acetylcholine levels

Though acetylcholine plays a key role in many aspects of your health, there are no dietary supplements that can directly increase its levels.

However, you can eat foods or take dietary supplements that indirectly increase the release of acetylcholine or inhibit its breakdown.

One of the easiest ways to raise acetylcholine levels is to consume foods or take dietary supplements that are high in choline &#; an essential nutrient that can be converted into acetylcholine (1).

Choline is present in many foods, including (6):

• Beef liver: 3 ounces (85 grams) contain 65% of the Daily Value (DV).
• Egg: 1 large hard-boiled egg contains 27% of the DV.
• Beef top round: 3 ounces (85 grams) contain 21% of the DV.
• Soybeans, roasted: 1/2 cup (86 grams) contains 19% of the DV.
• Chicken breast, roasted: 3 ounces (85 grams) contain 13% of the DV.
• Fish, cod: 3 ounces (85 grams) contain 13% of the DV.
• Shiitake mushrooms, cooked: 1/2 cup (73 grams) contains 11% of the DV.
• Kidney beans, canned: 1/2 cup (128 grams) contains 8% of the DV.
• Quinoa, cooked: 1 cup (185 grams) contains 8% of the DV.
• Milk, 1%: 1 cup (240 mL) contains 8% of the DV.
• Vanilla yogurt, nonfat: 1 cup (245 grams) contains 7% of the DV.
• Broccoli, boiled: 1/2 cup (78 grams) contains 6% of the DV.
• Brussels sprouts, boiled: 1/2 cup (78 grams) contains 6% of the DV.

Dietary supplements that can increase choline levels include alpha-GPC (L-alpha-glycerylphosphorylcholine), citicoline (CDP-choline), and choline bitartrate.

However, alpha-GPC and citicoline are typically higher in choline content per unit weight and are more easily absorbed than other forms (7, 8).

Another way you can indirectly increase acetylcholine levels is by taking supplements that inhibit enzymes that break down acetylcholine.

Certain supplements that may inhibit acetylcholine breakdown include (9, 10, 11):

• Ginkgo biloba (ginkgo)
• Bacopa monnieri
• huperzine A

However, it&#;s unclear how effective supplements that inhibit acetylcholine breakdown are at raising acetylcholine levels, compared with choline supplements.

Summary

Acetylcholine isn&#;t available as a dietary supplement, but its levels can be indirectly raised through choline intake, a precursor to acetylcholine, as well as supplements that inhibit acetylcholine breakdown.

Acetylcholine potential benefits

Increasing acetylcholine levels has been associated with several potential health benefits.

May aid memory and brain function

Research in animals and humans suggests that higher intakes of choline, a precursor to acetylcholine, may boost memory in people with memory issues.

In mice studies, supplementing with choline over their life span significantly improved memory and reduced the formation of amyloid-beta plaques &#; a compound that&#;s linked to the development of Alzheimer&#;s disease (12, 13).

A study in 2,195 participants ages 70&#;74 found that those with higher blood levels of choline performed significantly better in memory and learning tasks than those with low levels (14).

In addition, supplements that inhibit acetylcholine breakdown, such as Bacopa monnieri, Ginkgo biloba, and huperzine A, have been associated with improved memory and brain function (15, 16, 17).

That said, research on these supplements and mental performance is fairly new. More studies are needed before recommending them for this purpose.

May support mental health

Several studies suggest acetylcholine precursor supplements may help treat several mental health conditions.

An observational study with over 5,900 participants found that low blood levels of choline were linked to a higher risk of anxiety. However, it didn&#;t find a link between blood choline levels and depression (18).

Another study in 50 people with depression observed that people who took 200 milligrams (mg) of citicoline daily for 6 weeks alongside citalopram (a medication for depression) had less severe depressive symptoms than those who only took their depression medications (19).

There&#;s also some evidence that Bacopa monnieri and Ginkgo biloba may help reduce symptoms of anxiety, but more human research is needed (20, 21).

In addition, choline supplements are sometimes used to treat symptoms in people with bipolar disorder. However, there&#;s limited research in this area, and more studies are needed before recommending it for this purpose (22, 23, 24, 25).

May support a healthy pregnancy

Approximately 90&#;95% of pregnant women consume less choline than the suggested daily amounts (6).

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There&#;s some evidence that shows taking choline during pregnancy may support healthy fetal growth and improve fetal brain development.

One study indicated that supplementing with either 480 mg or 930 mg of choline per day during the third trimester of pregnancy significantly improved the infant&#;s mental function and memory at 4, 7, 10, and 13 months (26).

Another study in 69 pregnant women who were heavy drinkers found that taking 2 grams of choline daily from mid-pregnancy to birth significantly reduced the effects of alcohol exposure on the infant&#;s mental function (27).

Several other studies have noted that higher choline intake during pregnancy is associated with a lower risk of neural tube issues in infants (28, 29).

That said, other studies have observed no connection between maternal choline intakes and fetal brain development or neural tube issues, so more research is needed (30, 31).

Other potential benefits

Several other conditions may benefit from taking choline supplements, which may boost acetylcholine levels.

However, the relationship between choline intake and these conditions isn&#;t entirely clear, so more research is needed:

• Liver disease. A choline deficiency may cause liver disease, and higher choline intakes may be linked to a lower risk of liver disease and liver cancers (32, 33, 34).
• Heart disease. There&#;s some evidence that shows that choline may lower the risk of heart disease and stroke. However, the link is unclear, and other studies show mixed results (35).

Summary

Choline supplements, which may raise acetylcholine levels, have been associated with benefits, such as improved memory, brain function, mental health, and pregnancy support. Supplements that inhibit acetylcholine breakdown may help as well.

Acetylcholine supplement risks

As with any supplement, it&#;s important to talk to your healthcare provider before taking choline supplements or other supplements that raise acetylcholine levels.

In general, choline supplements, such as alpha-GPC and citicoline, are safe for most people and rarely associated with negative side effects.

However, consuming too much choline may have unpleasant and harmful side effects, such as low blood pressure, sweating, fishy body odor, diarrhea, nausea, vomiting, and liver damage (36).

Choline supplements have a daily upper limit of 3,500 mg, which is the most you can consume within a day that&#;s unlikely to cause harm (36).

That said, it&#;s very unlikely to consume this amount through diet alone. The only way to reach the upper limit is through taking supplements in large doses.

Bacopa monnieri, Ginkgo biloba, and huperzine A have been linked to side effects, such as nausea, stomach pain, diarrhea, and headaches.

These supplements may also interact with various medications, so it&#;s important to notify your healthcare provider of any herbal supplements you&#;re taking (37, 38).

Summary

Supplements that raise acetylcholine levels are safe for most people, but excessive amounts of choline may have unpleasant side effects. Always speak with your healthcare provider before taking supplements that raise acetylcholine levels.

Dosage and recommendations

Supplements that raise acetylcholine levels or inhibit acetylcholine breakdown can be purchased online and in select health food and supplement stores.

Choline supplements are your best bet for raising acetylcholine levels because choline acts as an acetylcholine precursor, and they typically have fewer side effects. They&#;re mainly available in capsule and powder form.

The best choline supplements for raising acetylcholine levels are alpha-GPC and citicoline, as they tend to be absorbed better and contain more choline per unit weight (7, 8).

Most choline supplement brands for both alpha-GPC and citicoline recommend taking 600&#;1,200 mg per day, which is equivalent to two capsules twice per day, depending on the brand.

Most studies on alpha-GPC and citicoline and mental decline use a dosage of up to 1,200 mg per day, which appears to be safe and well tolerated.

Though supplements such as Bacopa monnieri, Ginkgo biloba, and huperzine A may raise acetylcholine levels, it&#;s unclear what dosage is necessary to achieve this effect.

If you&#;re simply looking to raise acetylcholine levels, choline supplements are a better option.

Summary

Choline supplements are your best bet for raising acetylcholine levels, and most choline supplements recommend taking 600&#;1,200 mg per day.

The bottom line

Acetylcholine is a neurotransmitter (chemical messenger) that plays a role in many key aspects of health, such as muscle movement, thinking, and many other brain functions.

While acetylcholine supplements don&#;t exist, you can take supplements that may indirectly raise acetylcholine levels, such as choline supplements, and supplements that inhibit acetylcholine breakdown, such as Bacopa monnieri, Ginkgo biloba, and huperzine A.

However, choline supplements appear to be your best bet for increasing acetylcholine levels.

Aside from mental benefits, choline supplements have been linked to other positive effects, such as supporting a healthy pregnancy and aiding mental health, as well as potential heart and liver benefits.

However, avoid taking too much choline or any of the above mentioned herbal supplements as they may have unpleasant side effects. As with any supplement, it&#;s important to speak with your healthcare provider before taking it.

Choline is a water&#;soluble B&#;group vitamin, which humans must consume through their diet to remain healthy. Meat, eggs and yeast extract are great sources of choline, an essential component of cell membranes and also the precursor of the neurotransmitter acetylcholine (ACh). College students are traditionally introduced to synaptic physiology by study of the neuromuscular junction: a synapse where ACh is the neurotransmitter. One of the beauties of biology is quickly appreciated: the &#;signal&#; (the ACh) is terminated by the enzyme ACh esterase which hydrolyses ACh to choline and acetate. The beauty of this system is partly efficiency, because the choline and the acetate are rapidly (within seconds) recycled. Further thought raises a question about this piece of physiology which Bruhova and Auerbach explore with deep understanding in this issue of The Journal of Physiology (Bruhova & Auerbach, ): if ACh activates the receptor, why does not choline? The two are chemically similar and since ACh transiently reaches a concentration of over 1 mm in the synaptic cleft, then the choline concentration will transiently be high too. In fact choline can activate the receptor, but weakly, and it binds with much lower affinity.

So why are the interactions between the receptor and ACh or choline different? Insight into this question could be gained from study of crystal structures, e.g. of the snail ACh binding protein (Celie et al. ) with/without bound ligand. However, crystal structures are static, showing a frozen picture of the receptor, and give no information about the speed of receptor activation, receptor open probability, or the energetics of the protein conformational changes. These functional measurements are key to understanding the physiology. Bruhova and Auerbach answer this question using a combination of sophisticated molecular tools and clever analysis of single&#;channel patch&#;clamp electrophysiological recordings. Single&#;channel recordings, almost uniquely in biology, allow the observation, in real time, of the activity of a single protein molecule. This exquisite resolution provides the means to infer the affinity (binding free energy) of the receptor (with channel open or closed) for ACh or choline. Binding of ACh to the receptor and channel opening can be described by the mechanism:

A+R&#;k&#;12k+1 AR +A&#;2k&#;2k+2A2R&#;αβA2R&#;

(1)

where A represents ACh, R the receptor, and A2R* is the open channel conformation of the doubly liganded receptor. In adult mouse acetylcholine receptors (AChRs) the two transmitter binding sites are approximately equivalent and independent (Nayak et al. ) and so the agonist dissociation equilibrium constant K D = k &#;1/k +1 = k &#;2/k +2. However, this mechanism (eqn 1) is not the full story. One of the keys to the Bruhova and Auerbach analysis is the observation by Meyer Jackson of rare, unliganded AChR channel openings (Jackson, ). These happen, in the absence of ACh, when a receptor (R) spontaneously flips into the open channel configuration (R*). Although the importance of these was largely overlooked at the time, thermodynamic principles tell us that these events must happen (Monod et al. ; Karlin, ). The value of this observation has been elegantly developed in recent years by Auerbach and colleagues to give a more complete understanding of the energetics of AChR activation. In wild&#;type (WT) mouse muscle AChR, unliganded openings are extremely rare (happening about once every 15 min!). Bruhova and Auerbach use receptors with previously characterised combinations of &#;background mutations&#; that raise the probability of unliganded openings to measurable levels. These mutations do not affect the binding site (Nayak et al. , ) and so they allow the effects of a binding site mutation to be measured.

To understand the difference between ACh and choline binding, the channel gating constants E = β/α (E 0, E 1, E 2 for unliganded, monoliganded and doubly liganded receptors) were estimated from the channel open probability P o (E = P o/(1 &#; P o)) in the absence of agonist and at very high agonist concentrations. K D is calculated from E 0 and E 2 using a convenient shortcut: K D = (E 2/E 0)0.5. For example, E 2(ACh) = 25 and E 0(WT) = 7.4 × 10&#;7, so K D = 172 μm, and the agonist&#;binding energy is 0.59lnK D = &#;5.11 kcal mol&#;1. For choline E 2(Cho) = 0.046 and E 0(WT) = 7.4 × 10&#;7, so the binding energy = &#;3.25 kcal mol&#;1 (K D = 4 mm) and the difference in binding energy between ACh and choline of 1.86 kcal mol&#;1 corresponds to a 23&#;fold difference in affinity. Using energy changes as a way to describe agonist affinity is not common in physiology, but as Bruhova and Auerbach point out, it is no more complicated than using a Richter scale to describe earthquakes!

Bruhova and Auerbach use previously characterised mutations at the α subunit transmitter&#;binding site to explore the contribution of individual amino acid side chains to the overall binding energy of ACh and choline. Focusing on the aromatic rings of αY190, αW149 and αY198, each provides &#;50% less binding energy for choline compared to ACh. Considering the analogy of a weather vane on a clock tower, ACh is predicted (based on the structure of the snail ACh binding protein) to orientate itself in a North&#;Easterly direction (consider &#;North&#; as pointing towards the extracellular space) with the acetyl part of ACh forming an H&#;bond that helps to optimally orientate the agonist. The mutation analysis of the binding site predicts that the quaternary ammonium interacts preferentially with the aromatic rings of αY190, αW149 and αY198, with αY190 being deprotonated by K145. In contrast, because choline lacks the acetate moiety, its optimal position is in a Westerly orientation with its OH group able to H&#;bond with αW149 and the quaternary ammonium group interacting only weakly with αY190 and αY198. So the difference between ACh and choline turns out to be determined by the optimal position of the ligand in the binding pocket and is not just a matter of which way the wind is blowing when the agonist binds.

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