The neurotransmitter Acetylcholine (ACh) plays a leading role in alertness, focus, memory and mood. ACh also contributes to neuroplasticity that supports long-term potentiation needed to form long-term memory. And for a healthy, optimized brain.
ACh deficiency has been linked to ADHD, Alzheimer’s, dementia, Parkinson’s, and multiple sclerosis.
But you can’t take acetylcholine as a supplement. There is no such thing as “acetylcholine pills”, or “acetylcholine tablets”. But certain foods can help boost acetylcholine (ACh) by providing your brain with the choline it needs to synthesize ACh.
Food sources of choline are egg yolks, liver, milk and other dairy products, certain grains like quinoa and amaranth, bacon, edamame and cruciferous vegetables.
So many neurohackers use one of the choline supplements we discussed in Part 1 – Advanced Guide to Choline in Nootropic Stacks of this series to boost acetylcholine. Including:
And from our review, we know these nootropics often do so much more than simply increase acetylcholine in our brain.
But we have several other options available to help increase ACh release in the brain, inhibit its breakdown, encourage reuptake, stimulate ACh neuroreceptors, or provide the ingredients needed to create acetylcholine.
These nootropic supplements are considered cholinergic compounds. The following list is a brief description of both natural and synthetic nootropics that help acetylcholine in your brain.
For a more detailed review of each the following nootropics, simply click on the live link associated with that supplement. And you’ll go to a new page which will provide you with the nootropic’s history, mechanism of action, clinical studies, dosage notes, side effects and recommendations.
You can easily find these acetylcholine supplements on Amazon, GNC, The Vitamin Shoppe, Whole Foods and sometimes even Walmart. And the racetams are available at a few trusted online nootropic vendors.
Table of Contents
Supplements that Boost Acetylcholine
Alpha-Lipoic Acid increases acetylcholine production by activation of choline acetyltransferase and increases glucose uptake. This process supplies more Acetyl-CoA for the production of acetylcholine.[ii]
Researchers at Nizam’s Institute of Medical Sciences in Hyderabad, India gave 20 healthy male volunteers 250 mg capsules of standardized Ashwagandha extract for 14 days.
Significant improvements in reaction times were reported at the end of the trial. The study suggests that Ashwagandha extract improves cognitive and psychomotor (physical reaction) performance even when you’re in the best of health.[iv]
As an adaptogen, Bacopa helps balance the neurotransmitters acetylcholine, dopamine, and serotonin. And research shows Bacopa inhibits acetylcholinesterase (the enzyme that breaks down acetylcholine). As well as activates choline acetyltransferase. The enzyme that promotes acetylcholine creation.[v]
Researchers searched clinical studies to compare the cognition enhancing effects of Bacopa Monnieri and Ginseng to the popular smart drug Modafinil.
The team found that both Bacopa and Ginseng worked better than Modafinil for improving accuracy, memory and processing speed.[vi]
PS and PC are called phospholipids. And make up much of the inner and outer shell of brain cell membranes. Made up largely of DHA, these cellular membranes regulate entry into the cell, and control neuroreceptor function.[vii] Which facilitates cellular communication between, and within cells.
Phosphatidylcholine (PC) also contributes the choline needed to synthesize acetylcholine. And DHA regulates calcium oscillations, which are involved in neurotransmitter release, mitochondrial function, gene activation, oxidative stress and brain cell development and growth (BDNF).
A DHA supplement is one of the most important nootropics you can add to your stack. Recommended daily dosage is 1,000 mg of DHA per day.
Research also shows Gingko’s cognitive enhancing capabilities are due to its effect on the cholinergic system in your brain. It modulates pre-synaptic choline uptake and acetylcholine release, upregulates post-synaptic acetylcholine muscarinic receptors, and has an indirect effect on choline function by modulating the serotonin system.[ix]
One study using Cereboost™, a branded form of American ginseng (Panax quinquefolius), which has a high concentration of Rb1 ginsenoside, enhanced the activity of the enzyme choline acetyltransferase (ChAT). ChAT is the enzyme responsible for acetylcholine synthesis.
This ginseng supplement also restored brain microtubule-associated protein 2 (MAP2) as well as acetylcholine concentration.[x] And scientists just discovered that MAP2 is the main “traffic regulator” in neurons in the brain. This neuron traffic signaling system plays a key role in brain diseases like Alzheimer’s.[xi]
Gotu Kola is rich in triterpene saponosides. These triterpenes inhibit acetylcholinesterase (AChE). The enzyme that breaks down acetylcholine. Meaning more acetylcholine is available in your brain.[xii]
Huperzine-A is a natural compound extracted from the Chinese club moss huperzia serrata. Huperzine-A is an acetylcholinesterase (AChE) inhibitor. Which means it boosts levels of the neurotransmitter acetylcholine in your brain.
Nootropics users report Huperzine-A provides a boost in mental energy. Without the side effects normally associated with a stimulant. Improved cognition and clear thinking are common when using Hup-A. Many report a boost in short-term memory. Recall is better in the long-term.
Researchers at Walter Reed Army Institute of Research in Washington D.C. found Huperzine-A to be twice as effective in protecting soldiers against the lethal effect of the nerve agent soman, as the leading drug in that role called physostigmine.
Huperzine-A’s effects lasted for six hours compared to only 90 minutes for the drug.[xiii] Nerve gas used in chemical warfare attack the acetylcholine system in your body and brain.
Iodine is required for the production of thyroid hormones T4 and T3. Thyroid hormone receptors in the brain help regulate the production and use of all important neurotransmitters.
Thyrotrophic-releasing hormone (TRH) increases acetylcholine (ACh) synthesis.[xiv] One study showed that those with hypothyroidism had significantly decreased acetylcholine in the hippocampus. And that administration of T4 normalized ACh levels.[xv] Iodine is required to make T4.
Lemon Balm increases the activity of the neurotransmitter acetylcholine (ACh) in your brain. When your brain sends signals, it uses acetylcholine to keep the signals moving. But once used, your brain removes acetylcholine with an enzyme called acetylcholinesterase (AChE).
The rosmarinic acid in Lemon Balm is an AChE inhibitor. By inhibiting AChE, more acetylcholine is available to boost learning and memory. And Lemon Balm also has cholinergic receptor-binding properties. Which boosts the ability of ACh to bind to its receptors.[xvi]
Nicotine works primarily by upregulating nicotinic acetylcholine receptors (nAChR) in the brain. Boosting the release of acetylcholine (ACh), dopamine, serotonin, and glutamate. Increasing neural signaling of neurotransmitters and boosting alertness, cognition, memory and mood.
But studies have shown this upregulation of nAChR is dose dependent. And too much nicotine desensitizes these receptors.[xvii] So low doses of nicotine are key in using nicotine as a nootropic for cognitive benefit.
The National Institute of Drug Abuse conducted a meta-analysis of 41 double-blind, placebo-controlled studies conducted between 1994 and 2008. The analysis found significant positive effects of nicotine on fine motor performance, alertness, attention and accuracy, response time, short-term and working memory.[xviii]
Phosphatidylcholine serves as a storage pool for the choline needed as a precursor for acetylcholine (ACh) synthesis. ACh is synthesized from choline derived from the degradation of Phosphatidylcholine.
PC performs a 2nd important function in your brain. The hydrolysis of Phosphatidylcholine (by a process called phospholipase A2-catalyzed hydrolysis) is used to make the free fatty acids AA, oleic, linoleic, linolenic and DHA.
These free fatty acids facilitate synaptic transmission by targeting nicotinic ACh receptors using protein kinase C (PKC). This messenger system is needed for long-term potentiation (LTP). Researchers have determined that these fatty acids are critical for learning and memory.[xix]
PS is an integral part of the flow of crucial neurotransmitters like dopamine and acetylcholine. And phospholipids contain choline which is a precursor to acetylcholine (ACh). So PS will increase ACh levels in your brain. Affecting cognition, memory and mood. And reducing anxiety.
Rhodiola improves mood by influencing serotonin and norepinephrine levels in your brain. And the ‘feel-good’ opioids like beta-endorphins. It helps repair and grow new brain cells (neurogenesis). Rhodiola activates synthesis and re-synthesis of ATP. And reduces inflammatory C-reactive protein. Protecting your brain cells from oxidative damage.
Researchers at China Pharmaceutical University also found that Rhodiola extract inhibits acetylcholinesterase. Meaning it increases levels of available acetylcholine in your brain.[xx]
Muscarinic receptors are part of a large family of G-protein-coupled receptors (GPCRs) which are used as an intracellular secondary messenger system.
G proteins work by binding neurotransmitters, hormones, growth factors, cytokine, odorants and photons at the cell surface to the GPCR, and activating that receptor. Everything you see, hear, smell, or taste goes through this signaling process.
SAM-e also has a critical role as a methyl donor (called methylation) in the production and breakdown all the major neurotransmitters in your brain. Including acetylcholine.
Uridine is a precursor to the formation of CDP-Choline which is a precursor to the formation phosphatidylcholine (PC). PC separates into choline and sphingomyelin in your brain. Choline is then available to form acetylcholine (ACh). Optimal ACh levels is crucial for cognitive performance.[xxi]
Vitamin B1 (Thiamine)
Sulbutiamine is a synthetic derivative of Vitamin B1. It’s simply two Vitamin B1 molecules bonded together. This chemical bond helps thiamine more easily cross the blood-brain barrier. And is often a better alternative in a nootropic stack than just plain Vitamin B1 (thiamine).
Vitamin B5 (Pantothenic Acid)
Vitamin B12 (Cobalamin)
Vitamin B12 is a co-factor in the one-carbon cycle that is required for the synthesis of all major neurotransmitters in your brain including acetylcholine, dopamine, GABA, norepinephrine and serotonin.
Typical recommended dosage for nootropic benefit and optimal brain health is 100 mcg or 1 mg of Vitamin B12 (methylcobalamin) per day. Neurohackers older than 40 and those who have a problem with Vitamin B12 absorption should use 100 – 400 mcg or 1-4 mg of B12 per day. See the extended review of B12 for details.
Acetylcholine and the Racetams
Most of the nootropics in the racetam-family of compounds influence acetylcholine (ACh) in one way or another. Your chosen racetam could increase the synthesis of ACh. It could boost acetylcholine receptor density. Or increase the use of acetylcholine through the High Affinity Choline Uptake (HACU) process in parts of your brain. And even modulate the flow of acetylcholine.
This means that use of a racetam in your nootropic stack demands the addition of a quality choline supplement like Alpha GPC or CDP-Choline. To give your brain the ability to make the acetylcholine it requires.
If you neglect to use a choline supplement, you’ll not experience the full benefit of that racetam. And likely end up with a racetam-headache.
Please refer to my Advanced Guide to Choline in Nootropic Stacks for more.
Here are the best racetams for influencing acetylcholine in your brain.
Coluracetam boosts your brain’s choline conversion to acetylcholine (ACh) through the high affinity choline uptake (HACU) process.
Nefiracetam is a fat-soluble nootropic developed in Japan for the treatment of cerebrovascular disease. This racetam is structurally similar to Aniracetam. And helps modulate GABA levels in the brain which improves memory formation and recall, and provides anti-anxiety and antidepressant benefits.
Noopept does not appear in blood samples when taken as a supplement. Instead it elevates concentrations of cycloprolylglycine (CPG) in the brain.
Oxiracetam is a water-soluble racetam nootropic. And considerably more potent than Piracetam. Oxiracetam enhances choline-acetyltransferase (ChAT) in your brain.[xxv] ChAT is the enzyme needed to stimulate acetylcholine (ACh) synthesis.
Oxiracetam also enhances protein kinase C (PKC) which affects M1 acetylcholine receptors. Oxiracetam even demonstrates the ability to repair these receptors when damaged.[xxvi]
This translates into more receptors for each of these important neurotransmitters to bind with and boosts their effectiveness.
Phenylpiracetam has a positive effect on physical performance by increasing endurance, and reducing physical and mental fatigue. In fact, these effects are so potent that Phenylpiracetam has been banned from professional sports by the World Anti-Doping Agency.
Piracetam was developed by Romanian chemist, and the godfather of nootropics, Dr. Corneliu E. Giurgea in 1964. This is the first racetam ever developed.
Piracetam potentiates the flow of, and increases the effect of acetylcholine (ACh). And boosts the sensitivity and density of ACh receptors in the brain.[xxix]
Pramiracetam is a fat-soluble nootropic in the racetam-class of compounds. It has been shown to significantly increase High Affinity Choline Uptake (HACU) in the hippocampus. This action boosts acetylcholine (ACh) use which accounts at least in part for Pramiracetam’s ability to enhance cognition and memory.[xxx]
Pramiracetam also has a profound effect on the synthesis of the acetylcholine (ACh).[xxxi] Positively affecting encoding of new memories, concentration, cognition and neuroplasticity.
Not using a choline supplement while taking racetams is only one of the ways to you can deplete your brain of acetylcholine. Racetam-headaches happen because your brain will start to literally consume itself to get the building blocks it needs to make acetylcholine.
But what most neurohackers don’t realize is that we have easy access to plenty of anticholinergic medications that will do a great job of depleting your brain of acetylcholine. Drugs that decrease acetylcholine.
Any prescription or over-the-counter medication that blocks the action of acetylcholine is considered an anticholinergic.
These meds include antidepressants, antibiotics, antihypertensives, antipsychotics, and antispasmodics. If it starts with “anti”, it will very likely lower your acetylcholine levels.
Now, I’m not saying don’t use these medications. Just know how critical it is to replace the acetylcholine lost or suppressed while using it, with one or more of the supplements listed in this post.
Acetylcholine Supplements – The Last Word
Optimal levels of acetylcholine are critical for brain optimization and function.
Your diet, medications, some nootropics, and neurological disorders can all contribute to depleted levels of this critical neurotransmitter – acetylcholine.
We have dozens of supplements that can increase the synthesis of acetylcholine (ACh), increase density of ACh receptors, improve how ACh is used, and even amp-up the flow of acetylcholine in your brain.
But the way each of these nootropic supplements work vary from person to person. What works for me may not work as well for you. Experimenting is key to finding the best combination for your unique brain chemistry and genetics.
One final note – if you’re dealing with unusually significant memory loss. Memory loss that feels in your gut like it’s worse than it should be. Don’t take chances on trying every nootropic supplement and hoping for the best. Do yourself and your family a favor. And see a qualified neurologist.
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[iii] Choudhary M.I., Yousuf S., Nawaz S.A., Ahmed S., Atta-ur-Rahman. “Cholinesterase inhibiting withanolides from Withania somnifera.” Chemical and Pharmaceutical Bulletin (Tokyo) 2004 Nov;52(11):1358-61. (source)
[iv] Pingali U., Pilli R., Fatima N. “Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants” Pharmacognosy Res. 2014 Jan-Mar; 6(1): 12–18. (source)
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[vii] Litman B.J., Niu S.L., Polozova A., Mitchell D.C. “The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways: visual transduction.” Journal of Molecular Neuroscience 2001 Apr-Jun;16(2-3):237-42 (source)
[x] Shin K. et. Al. “Cereboost™, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection.” Regulatory Toxicology and Pharmacology. 2016 Jul;78:53-8 (source)
[xii] Orhan I.E. “Centella asiatica (L.) Urban: From Traditional Medicine to Modern Medicine with Neuroprotective Potential” Evidenced Based Complementary and Alternative Medicine 2012; 2012: 946259. (source)
[xiii] Saxena A., Qian N., Kovach I.M., Kozikowski A.P., Pang Y.P., Vellom D.C., Radić Z., Quinn D., Taylor P., Doctor B.P. “Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases.” Protein Science. 1994 Oct;3(10):1770-8. (source)
[xv] Wang N., Cai Y., Wang F., Zeng X., Jia X., Tao F., Zhu D. “Effects of thyroxin and donepezil on hippocampal acetylcholine content and syntaxin-1 and munc-18 expression in adult rats with hypothyroidism.”Experimental and Therapeutic Medicine. 2014 Mar;7(3):529-536. (source)
[xvi] Kennedy D.O., Wake G., Savelev S., Tildesley N.T., Perry E.K., Wesnes K.A., Scholey A.B. “Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties.” Neuropsychopharmacology. 2003 Oct;28(10):1871-81. (source)
[xvii] Gentry C.L., Lukas R.J. “Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure.” Current Drug Targets: CNS and Neurological Disorders. 2002 Aug;1(4):359-85. (source)
[xxi] Wang L., Albrecht M.A., Wurtman R.J. “Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat.” Brain Research. 2007 Feb 16;1133(1):42-8. (source)
[xxii] Martin P.R., Singleton C.K., Hiller-Sturmhofel S. “The Role of Thiamine Deficiency in Alcoholic Brain Disease” National Institute on Alcohol Abuse and Alcoholism nih.gov Retrieved May 5, 2016 (source)
[xxiii] Nishizaki T., Matsuoka T., Nomura T., Kondoh T., Watabe S., Shiotani T., Yoshii M. “Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission.” Alzheimer’s Disease and Associated Disorders. 2000;14 Suppl 1:S82-94. (source)
[xxiv] Gudasheva T.A. et. Al. “The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.” European Journal of Drug Metabolism and Pharmacokinetics. 1997 Jul-Sep;22(3):245-52. (source)
[xxvi] Fordyce D.E., Clark V.J., Paylor R., Wehner J.M. “Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice.” Brain Research. 1995 Feb 20;672(1-2):170-6. (source)
[xxvii] Belfiore P., Ponzio F., Biagetti R., Berettera C., Magnani M., Pozzi O. “Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7.” Neuroscience Letters. 1992 Aug 31;143(1-2):127-30. (source)
[xxviii] Firstova Y.Y., Abaimov D.A., Kapitsa I.G., Voronina T.A., Kovalev G.I. “The effects of scopolamine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task” Neurochemical Journal June 2011, Volume 5, Issue 2, pp 115-125 (source)
[xxix] Bering B., Müller W.E. “Interaction of piracetam with several neurotransmitter receptors in the central nervous system. Relative specificity for 3H-glutamate sites.” Arzneimittelforschung. 1985;35(9):1350-2. (source)
[xxxi] Brust P. “Reversal of scopolamine-induced alterations of choline transport across the blood-brain barrier by the nootropics piracetam and pramiracetam.” Arzneimittelforschung. 1989 Oct;39(10):1220-2. (source)
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