Nicotine, Cognition and Neuroprotection

My brain likes nicotine, it improves cognition and energy. Sadly, I quickly build a tolerance and it loses its effect. I have used huperzine, a Cholinesterase inhibitor with the ACH agonist Alpha GPC for years. There is not an issue with tolerance but it does not have the powerful cognitive boost of nicotine.

What other ACH agonists are as powerful as nicotine that do not build tolerance?

“These results suggested the acute exposure to nicotine was beneficial to protect the neurons, especially cognitive enhancement, and the elevated picolinic acid continually protected neuronal cognitive function after nicotine withdrawal.

Furthermore, the dynamic alterations of neurotransmitter metabolism induced by nicotine might be a possible protective mechanism of nicotine on hippocampal dependent cognition.”


When I was experimenting with nootropics a few years back I ordered some Nicorette nicotine gum and tried it for a while. The reason I stopped taking it was it produced an unwanted buzz and dizziness. I just tried it again today and got the same result.
I ordered it from Australia because it was much cheaper than my local pharmacy.

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I think those of us who have a relative deficit of a certain neurotransmitter benefit from increasing it. I apparently have an acetylcholine deficit because nicotine makes me very smart. I need to have about 2 mg of nicorette. Stronger than that makes me jittery. Same with too much huperzine or Alpha GPC

I’ve got overactive monoamine oxidase SNPs (MAO) so my SNPS lead to a deficit of dopamine. I need a lot of dopamine agonists. In addition to Seligilene, I take tyrosine and dopa macuna. On the other hand, my girlfriend has underactive MAO and she cannot do any dopamine agonists. When she was put on Ropinerole for restless leg, she got so anxious that she developed agoraphobia.


Mine is 4 mg. Maybe tomorrow I will try cutting one in half. 4 mg. is way too much for me.
I like tyrosine and take it as a balance for the tryptophan that I take.


There are Alpha 7 nicotinic receptor agonists that have been shown to improve cognition and modulate immune function that do not lead to tolerance. Some substances can activate nicotine receptors without nicotine. Apparently, allosteric agonists lead to tolerance but there are some ligand agonists that do not.

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery

"In the nAChR field, most of the attention on PAMs to date has focused on the α7 nAChR, though a few reports have identified selective α4β2* nAChR PAMs, with compounds divided into two classes based on their functional properties: type I and type II PAMs. Type I PAMs are defined as molecules that predominately affect the apparent peak current, agonist sensitivity, and Hill coefficient, but not the receptor desensitization profile, and type II PAMs are defined as compounds that possess the aforementioned properties described for type I PAMs, as well as the ability to modify the desensitization profile of agonist responses. It has been argued that type II PAMs are less prone to induce tolerance, which may occur after the chronic administration of nAChR agonists, whereas, type I PAMs may have advantages over type II PAMs as they can minimize potential calcium-induced cytotoxicity. See the following reviews to support the information in the earlier paragraphs related to the physiology and pharmacology of nAChRs and their role as therapeutic targets.

Are there any substances available that can activate these receptors?

I use nicotine gum on road trips because I can get to my destination before I build a tolerance. My goal is something I can buy that activates these receptors without developing tolerance.

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What is your favorite nootropic? I ran through many of the raceatams as well as the natural nootropics. Noopept was my favorite in Awaken Gold - on the pricey side. Most of the nootropics faded in value for me.

I really liked noopept. The first time I tried it I was blown away. Colors were vivid and focus was really improved. The first time I took it, I had to go to an exceptionally boring regular meeting and was able to be extremely focused.
The sad tale is, that was the only time it had that effect. On successive days the effect was less and less. I tried various suggested cycling and increasing doses, but, nada even after putting it on the shelf for weeks, it never had the same effect on me again.

I also continue to like piracetam, tried and true. Whenever I am stressed, I reach for the piracetam. It has no noticeable immediate effect, but always gives me some focus and more stamina after a few days.

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I had a similar experience with noopept. It must use up one of the brain transmitters and why it is short lived. Many of the nootropics require choline replacement to be optimal. Thanks for your insight!

What is your favorite choline supplement? What are your thoughts on dosage?

Right now I am taking Alpha GPC Choline as a supplement, not that I necessarily think it’s the best, but I have cycled through various choline supplements such as Phosphatidylcholine, Citicoline, etc., and can’t really say that I could ever feel the difference regardless of type, brand or dosage. I only take it two or three times a week because all of the nootropic sites say I should.

Jumping in, I take 1200 mg alpha-gpc daily. I posted elsewhere. It does produce a “more wired” mental state, buzz after I started taking it.

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I have the alpha GPC as well. I have to admit I jumped all in on the nootropics for about two years and slowly drifted off. I have found with my work and schedule, I only have time for one obsession and currently Rapamycin is taking up most of my free mind space. I have been trying some of the different mushroom combinations and have been impressed so far. Once my obsession with Rapamycin has calmed down, I probably will go back and look at the nootropics again. I did try Nuvigil about five years ago and it was a little heavy handed.

If not done already, this would be a great new topic.

Can you share some insight here? I take 1,000mg Lion’s mane.

I have tried three different brands - Genius, Four Stigmata and Stamets. I noticed some subjective (placebo?) with all of them. I usually take with coffee. Nothing all world, but probably the Four Stigmata or Genius brands had most noticeable focus and energy. I also tried cooking with some and failed at that. I don’t think I have taken more than 1,000mg of Lions mane - What are your thoughts so far?

Nothing discernible, like a lot of the inflammation targeted supplements in my stack I’ve added over time.

@MAC I went ahead and put up a new topic on nootropics and mushrooms to see if anyone else has experience with it.

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Many people on nootropics sites were saying they would get a headache from taking piracetam if they didn’t also supplement choline. I never suffered from headaches while taking piracetam at various dosages, so I didn’t pay too much attention to it.

Maybe, I will try to up my choline supplement intake and see if there is a subjective improvement. What are the best markers to look at to determine deficiency?

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I haven’t looked at the norprtopic literature in a year or so, but my guess would be that your choline dependent nootropic would stop working if you don’t supplement with choline. I never have any issues with piracetam either, but preferred phyenlpiracetam.

I really like nicotine as well. It helps my cognition and mood substantially. I was dismayed to learn that theres some evidence (not conclusive, but worth considering) that nicotine per se is causative of atherosclerosis. Would love to be wrong about this. Please post if you have counter-evidence or counter-analysis. Here’s what I’ve found in a few hours of research, presenting evidence in both directions.

  • Nicotine gum chewing has been shown to aggravate regional myocardial hypoperfusion in patients with known coronary artery disease ([65]).

  • Study “Using data from the United Kingdom’s Clinical Practice Research Datalink, this study aimed to evaluate CVD events and survival among individuals who attempted smoking cessation with the support of NRT compared with those aided by smoking cessation advice only.” Hazard ratio was 1.03–1.77 (95%) for ischemic heart disease (heart attack?) and 1.14–1.99 for cerebrovascular disease (?stroke) An explanation for the differences in all-cause mortality between treatment groups in the current study could be prescribing practices, with GPs preferentially prescribing NRT in patients with other smoking-related diseases, such as lung cancer. These patients could be more likely to be prescribed NRT, as this intervention has been shown to increase the likelihood of quitting by 50%–70%.10An alternative explanation is that the NRT cohort consisted of heavier smokers with a greater illness burden, who therefore had higher all-cause mortality compared with those receiving advice only. Both smoking and nicotine treatment have been found to increase heart rate and blood pressure.3437 The hemodynamic effects of smoking have been linked to nicotine, with heart rate found to increase with intravenous nicotine, nicotine nasal sprays, and nicotine chewing gum.3840 Nicotine was found to affect coronary artery constriction even at doses as low as 4 mg.41 These effects cause an increase in myocardial work and oxygen demand and result in impaired blood flow and oxygen supply to the heart. However, transdermal nicotine was found to have a lesser acute hemodynamic effect than smoking.42 Although there are not much data available on the effect of transdermal nicotine on coronary blood flow, Benowitz et al42 suggest that transdermal nicotine in smoking cessation treatment of patients with coronary heart disease is likely to be safer than cigarette smoking.

  • A study using the The Health Improvement Network (THIN) general practice database, included 33,247 patients taking NRT, and investigated acute MI, acute stroke, and death for each patient during exposed and unexposed time periods. The authors reported that although the incidence increased before exposure and decreased after exposure to NRT in the period of 56 days before and after first NRT prescription, NRT was not associated with an increase in risk of MI, stroke, or death.21

  • A second database study of 663 smokers with acute coronary syndrome that compared NRT versus no NRT reported no differences after 1 year for death, MI, repeat revascularization, or rehospitalization for angina, congestive heart failure, or arrhythmia.26

  • 2014 Metaanalysis of RCTs Relative Risk: nicotine replacement therapy (RR, 1.95; 95% CI, 0.26-4.30). So the study was rather under-powered.

  • Article 2012 suggest that nicotine, no matter how it’s delivered, can damage blood vessels.In short, nicotine modifies cell structure in a way that facilitates migration and invasion of cells that line the blood vessels. This enables a change in structures called podosomes, which lead to poor vessels and can cause the formation of plaque. Over time, plaque that’s built up can cause the arteries to harden, a form of heart disease called atherosclerosis. It can also block blood flow to the heart or brain, keeping oxygen from reaching those organs and causing heart attack or stroke.

  • “In Dr. Hai’s experiments, nicotine appeared to drive the formation of a kind of cellular drill called podosome rosettes, which are members of the invadosome family, consisting of invadopodia, podosomes and podosome rosettes. These specialized cell surface assemblies degrade and penetrate the tissue during cell invasion. Invasion of vascular smooth muscle cells from the middle layer of the arterial wall (media) to the inner layer of the arterial wall (intima) contributes substantially to plaque formation in atherosclerosis.”

  • Chi-Ming Hai, a molecular pharmacology professor at Brown University, believes the answer lies in nicotine. Hai exposed heart cells to nicotine and found that after 6 hours, podosome rosettes formed and ate through the tissue. The nicotine acted as “a kind of cancer of the blood vessel, which is waking up these cells and breaking them away from their surrounding matric [sic] and then migrating having an effect like it is almost like digging a hole through the wall,” he said.

  • Article found that the odds of a heart attack increased by 42% among people who used e-cigarettes. This increase in risk was on top of the increases in risk due to any smoking that the e-cigarette users were doing.

  • 2021 review “Although the initial presentations of nicotine-induced vascular dysfunction may be insidious (changes in vasoreactivity and vascular remodelling as discussed in this review), these changes contribute to the pathogenesis of serious medical conditions including atherosclerosis, abdominal aortic aneurysm, coronary artery disease and myocardial infarction.123–125”