Towards Better Cognition (17)

To read the first article in this series, click here.

To read the previous article in this series, click here.

To watch my accompanying YouTube video to this blog post, click here.


In an effort to improve their cognition through the cholinergic system, many cognition enhancers (e.g. much of the nootropics subreddit) will arbitrarily select a racetam and combine it with alpha-GPC. I think this is a misguided and suboptimal approach. In this final section of the series, I will comprehensively review the options that the cognition enhancer has and suggest my personal views.

There are precisely four entry points for the improvement of cognitive performance through the cholinergic system. First, we can consume choline to increase the quantity of acetylcholine available in the brain (e.g. alpha-GPC). Second, we can reversibly inhibit acetylcholinesterase, the enzyme that cleaves the acetate from acetylcholine, to slow down the degradation of choline in the brain (e.g. berberine and palmatine). Third, we can use compounds that sensitize cholinergic systems to agonists like acetylcholine (e.g. BQCA). And fourth, we can use compounds other than choline to directly agonize or antagonize cholinergic neurons (e.g. nicotine).


Choline is vital to human nutrition and choline deficiency causes liver disease. The nonalcoholic fatty liver disease that plagues 25% of the global population, 24% of the US population[1], and over 30% of Middle Eastern and South American people precipitates hepatic steatosis (NASH), which in turn precipitates fibrosis, cirrhosis, and hepatocarcinoma. Globally, 59% of those with NAFLD have progressed to NASH[2]. As the reader will remember, a month’s treatment with choline can cure even advanced forms of NASH. If liver protection is not enough of a motivation to optimize your choline intake, the DNA damage discussed earlier should be.

The complicating factor when choosing a choline intake level is that we are not created equal in our ability to produce choline and in our ability to methylate the various compounds crucial to our methylation cycles. Since choline donates methyl groups used for the methylation cycle, this second concern can cause our nutritional choline to deplete rapidly. Specifically, polymorphisms at the MTHFR, SLC19A1, COMT, MTR, MTRR, BHMT, SHMT1, and PEMT genes can dramatically increase nutritional choline needs. If choline requirements are not fulfilled, not only will liver disease and DNA damage progress, but we will be unlikely to have optimal acetylcholine levels in the brain.

The solution is to first analyze your genetics and decide on an intake level of phosphatidylcholine that should satisfy your nutritional needs. The most convenient way to consume higher levels of phosphatidylcholine without influencing the rest of your diet much is by including sunflower lecithin in your daily blended shakes. Depending on the severity of polymorphisms in the eight genes, you may also require supplemental methylcobalamin[3] (methylated B-12), riboflavin[4], and folate[5]. If you have impaired ability to methylate, you can also reduce the demands on choline for methyl donors by consuming a 5g daily serving of creatine[6][7][8].


Having satisfied your dietary choline requirement, you must decide whether to manipulate acetylcholine levels in the brain. There are reasons not to – as we have seen, some studies indicated that an overexpression of acetylcholine is correlated to depression. Anecdotally, I have noticed that people who raise acetylcholine levels very high can experience acute anxiety. Generally, one should likely only raise acetylcholine levels in the brain if one is not using an advanced protocol that selectively targets certain nicotinic and muscarinic receptors. Acetylcholine is indiscriminate and will agonize all receptors, which does not make for a tailored regimen and is from first principles unlikely to be optimal.

If you decide to manipulate acetylcholine, you can either increase acetylcholine synthesis or impede its breakdown. First, you can preferentially increase acetylcholine in the brain through L-alpha glycerylphosphorylcholine (alpha-GPC) supplements. Alpha-GPC is a precursor to acetylcholine. Supplementation with it has been shown to improve cognitive[9] and athletic performance[10]. It appears to be the most effective dietary tool to preferentially increase acetylcholine in the brain[11].

Second, you can take the therapeutic route of Alzheimer’s patients by inhibiting the breakdown of acetylcholine in the brain. From our review, you will note that the pharmaceutical options, namely donezepil, rivastigmine, and galantamine, are not very well tolerated and are slightly toxic. Of them, the best tolerated is donezepil, which is unfortunate, since galantamine has the added benefit of sensitizing cholinergic receptors to choline.


A better choice is to develop a personalized regimen combining huperzine A, ginkgo biloba, bacopa monnerie, berberine, and palmatine. Huperzine A is particularly attractive because of its secondary effect in partially blocking NMDA receptors. It is tempting to speculate that this may offer a neuroprotective effect from excitotoxicity over the long-term.

Gingko biloba is the most commonly used reversible acetylcholinesterase inhibitor in the cognition enhancement community. It is the most powerful inhibitor on the list and is an attractive option for frequent use because of its phytochemical-based antioxidant effects[12], which appear significant. On the other hand, bacopa’s profile makes it less attractive for frequent use. Bacopa’s anxiolytic effect likely depends on receptors that downregulate in response to stimulation, which means that chronic use will produce downregulated receptors. Intermittently, it could be used specifically for the anxiolysis, as it has a bioequivalence to weaker benzodiazepines and a comparable effect to ashwagandha root[13].

Though weaker than gingko biloba, berberine and palmatine are attractive reversible acetylcholinesterase inhibitors for long-term use. Berberine not only reduces amyloid-β aggregation, but it produces a weak activation of the adenosine monophosphate-activated protein kinase (AMPK) pathway that is a primary target of the drug metformin and a longevity-producing pathway in humans. Berberine also weakly inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), the target of the expensive (i.e. $5000 per annum) new class of cardiovascular medications such as Repatha. (Unless you qualify as having hypercholesterolemia, it is presently impossible to have insurance cover PCSK9 inhibitors, making berberine an attractive albeit less potent alternative). On the other hand, palmatine’s cholinesterase inhibition is attractively coupled with its chemoprotective effect, shown in vitro with prostate cancer cells. Together, berberine and palmatine should be considered synergistically longevity promoting.

People respond differently to these five herbal extracts. I suggest trying gingko biloba first to observe its acetylcholinesterase inhibition alone. After removing it for a period, you should experiment with huperzine A to observe the secondary effect on NMDA inhibition. If you find huperzine A’s effect favorable, consider combining it with berberine and palmatine, before adding back gingko if you require a stronger effect. While huperzine A, gingko, berberine, and palmatine could be used chronically, I suggest using bacopa sparingly to maintain optimal receptor function.

Note that users of racetams frequently consume alpha-GPC because of a single study[14] that indicated that a racetam can deplete acetylcholine levels, while they should likely be using an acetylcholinesterase inhibitor instead.


While high levels of choline have been shown to correlate with a depressive phenotype, nicotine has never exhibited these effects. Moreover, while nicotine upregulates cholinergic receptors, acetylcholine has not been shown to do the same. Anecdotally, I have observed symptoms of cholinergic receptor downregulation in people who megadose acetylcholine precursors like alpha-GPC, though this does not appear to happen with people who inhibit acetylcholinesterase. For these two reasons alone, there is good reason to think that increasing acetylcholine levels past a certain point will have reduced marginal benefit as compared to nicotine and its analogues.

Before discussing the nicotinic analogues and the single interesting muscarinic agonist of interest, it is worthwhile to note that antidepressants likely cause an upregulation of cholinergic receptors through their antagonism of said receptors. As viewers of my YouTube channel will know, I have a fondness for selective serotonin reuptake inhibitors (SSRI’s), which I view as potent cognitive enhancement molecules.

I will produce an exhaustive literature review on the serotonergic system at a later date, but for now, it is tempting to speculate that they exert a net positive impact on the cholinergic system. Anecdotally, I am certain that their antagonism of the cholinergic receptors is partial, as nicotine produces a cholinergic response on attention even while being co-administered with an SSRI. Overall, they may enhance nicotine’s effects, yielding a synergistic upregulation of nicotinic receptors while not fully inhibiting their stimulation.


Agonizing the M1 receptor may improve cognition, limit amyloid-β aggregation, and attenuate liver injury. The problem with doing so with available synthetic compounds is that nearly all of them antagonize the dopamine D2 receptor. While antagonizing the receptor may yield a short-term benefit in receptor upregulation, dopamine receptors need to be free to function for long-term habit development, clarity of thought, and driven behavior. Only the Vanderbilt University compounds VU0357017 and VU0364572 exhibit sufficient selectivity and only the latter is devoid of an effect on dopamine receptors. For this reason, I think VU0364572 can be a useful compound for long-term use towards cognitive enhancement and neuroprotection. To my knowledge, no one has publicly admitted to self-experimenting with these novel muscarinic agonists yet.


Of the nicotinic cholinergic agonists, the most attractive are the Abbot Labs analogues ABT-418 and ABT-089, the University of Florida analogue GTS-21, SEN1233, lobeline, and, of course, nicotine. ABT-418 agonizes α4β2, α7, and serotonin 5-HT3. Its effect on 5-HT3 makes it undesirable for chronic use, in a similar fashion to bacopa. ABT-089’s effect on α4β2 and α6β2 is cleaner and thus more attractive. It is unusual in its effect on the α6β2 subtype, though it misses an effect on the α7 receptor type, a receptor class that has been shown to have play a major role in cognition.

GTS-21 preferentially agonizes α7 over α4β2 receptors, making it potentially couplable with ABT-089. The highly specific SEN12333 is a better compound for synergistic use, as it only agonizes α7 receptors, although there are some less known molecules with similar selectivity but greater affinity for the α7 receptors (e.g. compound 45 has an 8x greater affinity[15]). Loneline is attractive because it is not a synthetic compound and it has complex effects on the brain. While it diminishes the effects of amphetamines and nicotine, it independently produces dopaminergic effects. To me, it seems like a messy compound that would be better used alone.


This series of blog posts acted as both a literature review and a history of the cholinergic system as it pertains to cognitive enhancement. In the next series, I will use a similar approach to review the serotonergic system.

To return to an overview of the blog series on the cholinergic system, click here.

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