How to Leverage Acetylcholine for Cognitive Enhancement
Understanding Acetylcholine and Cholinergic Nootropics
Acetylcholine is the most overlooked neurotransmitter for cognitive enhancement. Most people seem to hyper-fixate on dopamine because it's a well known molecule in the mainstream, but to ignore acetylcholine is to ignore a molecule that has a profound effect on focus, memory, and general cognition.
Acetylcholine (ACh) is an incredibly unique molecule in the body with a wide range of functions. In the brain, it supports the various cognitive functions mentioned above and influences REM sleep, but ACh is also responsible for making our muscles contract and controlling the function of our autonomic nervous system (fight or flight/rest and digest). While those last two functions are interesting on their own, I want to focus on ACh’s actions in the brain here because supplements and herbs that manipulate cholinergic neurotransmission are incredibly useful tools and should be a part of even the simplest supplement stacks aimed at improving cognitive function.
But what exactly makes ACh such a great target for cognitive enhancement?
It primarily has to do with where it is released in the brain. Cholinergic neurons (those that produce and release ACh) reside in the basal forebrain and brainstem and project to various regions of the brain, primarily the hippocampus and cortex. These target regions implicate ACh in learning/memory, focus, arousal, and cognitive performance.
The hippocampus is the brain’s memory center (discussed more in depth in my how to improve memory article linked here), and it’s densely packed with ACh receptors and receives a ton of cholinergic input. While the cortex, especially the prefrontal cortex, is involved in higher level thinking, reasoning, and arousal. As a result, increasing ACh neurotransmission in the brain is going to enhance cognition greatly in several ways, which is what makes ACh is such a useful nootropic target.
Before we can dive into tools that leverage ACh for cognitive enhancement, we first need to know a little bit of background on how ACh functions as a neurotransmitter. This way, we will understand how these compounds work and synergise with each other to enhance our memory and cognition.
Acetylcholine Synthesis
Interestingly, ACh is the only major neurotransmitter that is not derived from an amino acid. Instead, it is synthesized from the precursors choline and acetyl-CoA.
Acetyl-CoA is generated in the mitochondria as a product of glycolysis. From there, it is transported into the cytoplasm of the synaptic terminal to be combined with choline by the enzyme choline acetyltransferase to make ACh.
The choline necessary for this synthesis is obtained by either uptake from the extracellular space or the internal breakdown of phosphatidylcholine, a molecule that is abundant in cell membranes. While choline can be produced endogenously in the liver, the body can't produce enough to meet needs, so we must get at least some choline through diet to support healthy ACh levels. Adequate intake levels of choline are 550mg/day for adult males and 425mg/day for adult females (500mg+ if pregnant or breastfeeding) as determined by the Food and Nutrition Board of the Institute of Medicine [source]. Choline is found in many different foods, but is highly prevalent in egg yolks and meat, so just a few eggs and/or a good amount of meat per day is enough to hit that.
This is just the established “adequate intake”, yet most people still aren’t hitting these numbers. Going above that threshold is going to be beneficial for not just acetylcholine levels, but for providing phosphatidylcholine to support the cell membranes of our neurons and all other cells throughout the body.
Acetylcholine after release
Like all other neurotransmitters, once synthesized, ACh is packaged into vesicles and subsequently released in an action potential dependent manner.
(For more information on this process, I recommend checking out the three part Neuroscience Crash Course series I put out here on Substack. Link to part 1 here)
After its release, ACh binds to receptors on the postsynaptic neuron as a way of transmitting its message, typically increasing the likelihood of the postsynaptic neuron firing (not always true because there are inhibitory metabotropic ACh receptors). However, immediately after ACh molecules are released into the synaptic cleft, the enzyme acetylcholinesterase (AChE) begins breaking them down into choline and acetate. This serves as a way of terminating the signal the presynaptic neuron is sending and allows the choline to be reuptaken and recycled into more ACh. This is doubly important since there is no ACh reuptake transporter like there is with most other neurotransmitters to help with this recycling process, just a choline transporter.
Fun fact, AChE is one of the fastest enzymes in the body, breaking down 5,000 molecules of ACh per second.
Because of the importance AChE plays in terminating cholinergic signals, inhibiting this enzyme is a common mechanism among nootropics and drugs prescribed to treat the cognitive decline and memory deficits associated with dementia (e.g. Donepezil and Galantamine).
Nootropics and Supplements that Target Acetylcholine
Now that we have a fundamental understanding of the cholinergic system, it should be clear that there are three primary ways to manipulate it to reap the cognitive enhancing benefits;
Increase synthesis and release
Inhibit breakdown in the synapse
Directly activate receptors
Let’s go through each of these individually, with examples, and discuss potential synergies.
Increase Synthesis and Release
In order to increase ACh synthesis and release we are going to want choline sources. Yes, choline can be obtained through dietary sources (and I do recommend getting more than the adequate intake from food sources), but choline containing supplements are going to be superior for quick hitting cognitive enhancement.
There are several choline containing supplements out there, but the top two in my eyes are;
CDP-Choline (aka Citicoline or Cognizin) is a unique nootropic compound that provides both choline and cytidine, the latter of which can be converted into uridine. While choline supports ACh activity as a precursor, uridine has a dual neuroprotective and cognitive enhancing effect by increasing the synthesis of neuronal membranes (choline can contribute to this as well through conversion to phosphatidylcholine). Together, these two molecules support memory and overall cognitive function by promoting ACh activity directly and increase the potential for neuroplasticity.
Alpha-GPC works similarly to CDP-Choline, except instead of supplying cytidine alongside choline it’s focused on providing as much choline per gram as possible. Each Alpha-GPC molecule contains a much larger percent of choline than CDP-Choline per weight (40% vs 18%), which means you’d need a much smaller dose of Alpha-GPC to get the same amount of choline.
Both of these compounds provide bioavailable choline which readily crosses the blood-brain-barrier. This contributes to increased cholinergic transmission and neuroprotection by supplying choline and their accompanying molecules that aid in cell membrane synthesis. The primary difference between the two is that CDP-Choline trades total choline per gram of supplement in exchange for packing two nootropic compounds in one (choline and cytidine). In my opinion, this makes Alpha-GPC better for acute cognitive enhancement, while CDP-Choline is the superior everyday choline supplement.
Inhibit Breakdown in the Synapse
While ACh precursors are a great way to support cholinergic neurotransmission and even push it a bit, inhibiting AChE is where we really start to see a marked increase in cholinergic activity (unless you were previously choline deficient). By inhibiting the breakdown of ACh after its release, this mechanism indirectly increases the activity of ACh on postsynaptic receptors by leaving a higher concentration of ACh in the synapse for longer.
There are many herbs and other compounds out there that inhibit AChE, but some of the most well known and popular over the counter ones are;
While Huperzine–the most potent–provides the most bang for your buck AChE inhibition wise, the others have a host of other cognitive enhancing mechanisms alongside a more mild AChE inhibiting effect. Which you should choose will depend on what your goal is.
Chasing pure cholinergic activity? Go for Huperzine A
Want a more well rounded experience? Try the others
Directly Activate Receptors
There is one infamous nootropic out there that is well known to directly activate a subtype of ACh receptors, and that’s nicotine. Nicotinic acetylcholine receptors actually got their name because of nicotine’s binding affinity for them.
Nicotine is going to be the most potent cholinergic nootropic that’s readily available over the counter. It binds to and activates nicotinic ACh receptors, which directly increases cholinergic activity without the need to alter ACh levels at all.
The obvious caveat with nicotine use is that it’s incredibly addictive and is easily abused if proper precautions are not taken. If you’re using nicotine enough to become addicted, it has likely lost most of its potency as a nootropic and will require larger and larger doses to be effective which pushes you further into physical dependency.
No one wants that…
The best way to avoid addiction and tolerance with nicotine is to limit its use to a set number of days per week. For me, it’s three days a week at a maximum and always less than 3mg per day. Maybe I could get away with four, but the risk outweighs the reward by a long shot when I have other nootropics in my arsenal for those other days if needed/wanted.
This isn’t an endorsement of nicotine use, and I definitely recommend avoiding it if you don't have the self control or desire to limit your use.
Potential Synergies
The obvious synergy of the above mechanisms is going to be stacking an ACh precursor with an AChE inhibitor. The combination of increased ACh synthesis/release and inhibiting its breakdown in the synapse is a match made in heaven. With a pairing like this you’re able to use a lower dose of each compound for a more efficacious and prolonged effect since their combination results in a 1+1=3 effect.
A common stack I’ll run is Alpha-GPC + Huperzine A. I was previously underwhelmed by Alpha-GPC, and while it definitely provided me with some notable cholinergic activity it was nothing to write home about. However, once I paired it with Huperzine I realized its full potential. I was able to use less than half of the dose for each of these nootropics to achieve a more potent, fluid cholinergic state that lasts longer, and at this point it's rare that I use one without the other. The same thing will apply to any choline source and any other AChE inhibitor.
Conclusion
Acetylcholine is an incredibly underappreciated neurotransmitter and has tons of potential as a target for improving memory and general cognition. Your ability to manipulate it relies simply on knowing what mechanisms to target (precursor, AChE, receptors) and what compounds have said mechanisms. The example compounds listed above should be all you really ever need to take advantage of ACh in its entirety (even without nicotine), but knowing the mechanisms is beneficial if you’re trying to understand the potential benefits of an herb/supplement you're looking into.
This article is the first in a two part series looking at how to manipulate various neurotransmitter systems to benefit you cognitively in a nootropic context. Next, we’re looking at everyone’s favorite, dopamine, which gets a little more complex but with more potential benefits. After that, we’ll tie it all together with a “How to build your own nootropic stack” post, so stay tuned for those coming soon.
That’s all for now. Thanks for reading,
-BowTiedNeuron
Disclaimers
This article is for education purposes only and is not medical advice. Always consult your doctor before starting any new supplements.
This article contains affiliate links that will reward me with a commission if you choose to use them, however it comes at no cost to you and helps support my content.
Cool post, question, is there a relationship between default mode and the amount realesed of acetylcholine? If yes then would it make sense to take noon tropics before going to sleep?