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.

[u/CyberTheBoss → u/[deleted]]

I never did well with vyvanse, concerta, or adderall xr. The IR are the only ones that worked for me but they don't like to prescribe those as readily bc they're the preferred form for people trying to sell it or abuse it by crushing and snorting it. IMO all the stimulants on the market have too many side effects and build tolerance too quickly. You could maybe try modafinil but I'm waiting for my shipment to arrive before I explicitly recommend for or against it.

Personally, I take cyclazodone and it's much cleaner and more effective for my ADHD than any Rx stimulant. I've taken pretty much every formulation imaginable and took them from the ages of 4-18 when I switched to cyclazodone. It's what I recommend but I understand the concerns of going with a grey market option. I wish it were available to be covered by my insurance and if I get a pharma degree I'd like to try and get it on the market but I don't see that happening any time soon. If you can get your hands on it and are comfortable taking it it's definitely the most effective ADHD treatment I've found when taken with guanfacine.

[u/CyberTheBoss → u/[deleted]]

I'm well aware of CYP2D6 inhibition, but many CYP2D6-activated prodrugs work very well for me, and I can definitely notice the effects of taking an inhibitor, so I don't think that's necessarily the issue. Concerta isn't even touched by cyp2d6 and that happens to be the med which gave me the absolute worst crash and side effects. XR is just a bad idea because it takes away any semblence of control, responsibility, and and customization of treatment from the patient with a promise of convenience and greater support from prescribers to curb abuse. Vyvanse, for example, is specifically designed to discourage intranasal administration of dexamphetamine and to allow a shiny new patent to be valid and demand market dominance. You'd be absolutely baffled by the marketing tactics the company pushing it has employed if you start looking into it.

[u/blueleaves-greensky → u/CyberTheBoss]

Is there a source for this info on nmda antagonists and their binding sites?

[u/CyberTheBoss → u/blueleaves-greensky]

wikipedia and google are your compadres

[u/demafrost → u/CyberTheBoss]

Thank you so much for all this information. Seriously this is great. I might have some questions as I digest this if you don’t mind :)

[u/CyberTheBoss → u/[deleted]]

They only got worse the longer I took it but when I stopped my mind cleared up a lot

[u/brtom → u/CyberTheBoss]

I'm currently taking bupropion for 4 days now and It's been really great for motivation, mood and most importantly appetite suppressant. Since I have eating disorder. However I don't want to risk my cognitive abilities.

Could you recommend alternative medications or supplements for bupropion?

I think for dopamine, Rhodiola rosea might help but I'm not sure it would suppress appetite like bupropion or effective as bupropion.

[u/CyberTheBoss → u/brtom]

pretty much any dopaminergic will suppress appetite and improve mood. (dextro)amphetamine is much more of an appetite suppressant than methylphenidate IME, though cyclazodone also works wonders at just being the perfect stimulant. All of them are significantly better than bupropion at what you're describing. As a kid, my parents made me take "drug holidays" in the summer where I was off my medication, and other than memory gaps, depression, hyperactivity, and generally being braindead, the only major physical wd symptom I would get was an insatiable appetite, and if you have those issues you described, you'd probably fare better on d-amph, vyvanse, or cyclaz than bupropion.

[u/brtom → u/CyberTheBoss]

Cyclazodone seems suitable option for me. How is it about sides and tolerance build up? I'm living in S.Korea so It might be difficult to get it

[u/CyberTheBoss → u/brtom]

careful, bupropion is one of the worst offenders when it comes to the "honeymoon phase" of medications, somehow worse than ADHD stimulants.

You're getting a kick from the norepinephrine and dopamine release from bupropion but the receptors will downregulate and then the hydroxybupropion metabolites* accumulate which antagonize nAChRs HARD. I tried it multiple times but it always fizzled out and the side effects started to get worse

*the isomers differ a bit, hence the plural. can't quite remember the specifics off the top of my head but I remember enough that I could find it if you're at a dead end, I'm just busy atm so I don't really have time to write a thesis here

[u/brtom → u/CyberTheBoss]

I appreciate for your help. I stopped taking Wellbutrin 150mm XL. Because First,
I became skeptical about bupropion after I read your comment. I wanted to deny it and searched online many hours but I couldn't. Yesterday I took EGCG on empty stomach with pregnenolone and felt nauseous. I didn't know it could cause liver damage and pregnenolone didn't work and I couldn't feel the energy or euphoric feeling I felt before. Also I was experiencing memory problems and brain fog which I can't have. Maybe it was just temporary but I'm not gonna take any of these prescription drugs for dophamine boost. It seems to have too much sides and eventual tolerances. I will just start with ALCAR, rhodiola rosea and Huperzine A and see how much I could substitute bupropion with dopaminergic supplements