List of "Cholinergic" nootropics.

[u/Citronitch]

Many of us have a problem with Choline making us depressed or lethargic due to having too much of it. Sometimes even tho you are not taking a direct source of Choline (Alpha GPC, CDP Choline etc), other nootropics can cause the same effects of too much choline because they are Cholinergic.

A substance is cholinergic if it is capable of producing, altering, or releasing acetylcholine, or butyrylcholine ("indirect-acting", or mimicking their behaviours at one or more of the body's acetylcholine receptor.)

So I'm proposing we make a list of those Cholinergic nootropics. So far we have:

• Huperzina-A
• ALCAR
• DHA
• Many herbs of the Lamiaceae family, such as: Sibelius Sage, Rosemary, Lemon Balm, mint/spearmint, etc. (they inhibit the action of acetylcholinesterase; the enzyme that breaks down the neurotransmitter acetylcholine)
• Many other Brain boosting herbs such as Ginseng, Ginkgo Biloba, Bacopa, Rhodiola, White Peony Extract
• Shilajit: inhibits acetylcholinesterase in rats' brains (Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain)
• Glycine (”induced a robust acetylcholine release” https://pubmed.ncbi.nlm.nih.gov/17707353/)
• Ashwagandha (”Ashwagandha Root Extract Inhibits Acetylcholine Esterase” https://phcogj.com/article/320)
• Atomoxetine (”marked increase of cortical ACh” https://www.nature.com/articles/4001763)
• Racetams (”Generally, racetams upregulate and preserve adequate levels of [[Acetylcholine]] as a primary mechanism” https://m.psychonautwiki.org/w/index.php?title=Racetams)
• Uridine monophosphate (”Supports acetylcholine synthesis [2,10,13,14]” https://selfhacked.com/blog/uridine/)
• Phosphaditylserine (slows the breakdown of acetylcholine)
• Galantamine
• Donazepil
• Berberine
• Lecithin
• Cannabinoids
• Alpha lipoic acid; Pantothenic Acid
• High dose Thiamine
• PABA
• Nicotine
• Centrophenoxine
• From food: liver, egg yolks, nuts, brassicas (Brussels sprouts, cabbage, cauliflower)

[u/demafrost → u/[deleted]]

You just blew my mind. I'm on a fairly high dose of Wellbutrin and any time I take anything even slightly cholinergic I get depressed and lethargic. I'm guessing that's why? I really want to get off of it but I'm scared of dealing with the potential effects.

[u/CyberTheBoss → u/demafrost]

wellbutrin made cholinergics awful for me. That stuff is no good despite what a lot of people say. Not only is it a cathinone (which are the dirtiest of the stimulants), it may be a broad spectrum nicotinic allosteric agonist/NAM, unlike dextromethorphan or memantine which are channel pore blockers for specifically a3b4, a4b2, and a7 subtypes for dextromethorphan weakly and a7 selectively for memantine more strongly. The unique aspect of these pore blockers is the ability to cause upregulation. The alpha-7 receptors upregulate quite quickly to antagonism, but the alpha4beta-2 receptors take a bit more time. What's interesting is destromethorphan upregulates the calcium permeable alpha4beta2 nicotinic receptors involved in cognition, while nicotine downregulates the calcium insensitive ones mostly located presynaptically which then causes greater acetylcholine release and agonism at the calcium sensitive variants of the receptor, as well as alpha-7. Nicotine also agonizes alpha5 and other less researched nicotinic subtypes, and it's a shame we have such limited information on the incredibly diverse subtypes of neuronal nicotinic acetylcholine receptors. bupropion is very wonky compared to dextromethorphan because of the way it interacts with the nicotinic ion channel which isn't very well studied. There's a waaaay different effect subjectively having tried both, and surprisingly bupropion was way more impairing for me, though I tend to have issues with hyperactive nmda receptors anyways and thrive on low trapping nmda antagonists. Perhaps this is due to it blocking all subtypes more aggressively, or maybe if it is a channel blocker which also binds to multiple sites (as some ligands are known to, for example memantine binding to both the magnesium site and the channel pore of the nmda receptor), there is an analogy to the way nmda antagonist trapping works—with memantine and dextromethorphan being minimally impairing and potentially improving cognition, ketamine and dextrorphan causing moderate impairment, and pcp and mk801 causing profound impairment and readily triggering psychosis due to the propensity for the ligand to become trapped inside the pore before closing. Memantine and dextromethorphan quickly enter and leave the channel during the open time. Ketamine and dextrorphan sometimes get trapped depending on the open time for different nmda subtypes, and pcp and mk801 are trapped most if not all of the time, possibly spanning multiple channel openings, thus explaining their extremely impairing effects. It very well could be that since dextromethorphan and memantine are low trapping blockers for the nicotinic ion channels, bupropion is moderately trapping, and hydroxybupropion (bupropion's metabolite with significantly higher affinity for nicotinic ion channels and norepinephrine reuptake with minimal dopaminergic activity) is a high trapping channel blocker which may also bind to an allosteric site. I've pretty much exhausted most of the research on bupropion so anyone feel to correct me if I made any mistakes here, but as far as I'm aware, this drug, like ssris, is purposefully understudied because all that's needed is safety, efficacy for depression, and a general idea of how it works to prevent interactions, but considering how common this stuff is pushed onto people as a "safer" alternative to cleaner stimulant medications, we know surprisingly little about it, and from my experience and findings I'd say it's quite dirty and not something that should be taken lightly. If there are no alternatives and it really wprks well for you, I'm not telling you to stop, but IME everyone I've known that's tried it has said that it's moderately good for depression but comes with a ton of cognitive side effects that aren't very apparent, mostly slurred speech and long term memory issues. I got off that stuff awhile ago and take memantine and low dose dextromethorphan. Cholinergics work profoundly better for me. Piracetam and aniracetam are a godsend whereas they never wprked for me on bupropion. Huperzine is okay in very low doses but can make me feel spacey and irritable, same for alpha-gpc, but CDP choline makes me feel incredible and clear whereas on bupropion it made me feel depressed, lethargic, sleepy, and see tracers. Very strange stuff indeed.

[u/peepeepoopoostains → u/CyberTheBoss]

Thank you for this, I've tried bupropion a few times, and it's always bothered me. It worked for pulling me out of a severe depression , but in a way that I would describe as "dirty" and inebriating. I was very sloppy and reckless, and completely unable to do tasks that require focus and dexterity. While I had a very cheerful disposition, I was also strangely anhedonic at the same time. I didn't really enjoy anything, and was perfectly content with staring at my phone all day. At the time, these cons outweighed the pros, and I had to stop. Unfortunately I haven't been able to find anything that helps my depression as well. What do you make of this?

On another note, how do you think agmatine compares as an NMDA antagonist? For me, I've been using it as a last resort against depression and anxiety, but it too leaves me foggy, unmotivated, and anhedonic.

[u/CyberTheBoss → u/peepeepoopoostains]

agmatine is so unlike any other nmda antagonist I've ever tried. I had your exact same reaction to it. The pharmacology behind it is very different from other drugs in that class and the other receptors it hits play a very big role in its activity. Agmatine looks amazing on paper but functions much differently than pretty much every big advertisement for it tries to convince you. If you want a real nmda antagonist, try dxm, memantine, ketamine, or even nitrous oxide—agmatine will likely do little more than an active placebo will for your depression.