#22

There is growing evidence that apart from direct mechanisms of SGLT2 inhibitors in the central nervous system, they also exert a beneficial pleiotropic effect. In silico studies indicate that flozins have the molecular ability to inhibit acetylcholinesterase. Canagliflozin was even called a ‘dual inhibitor of SGLT2 and AChE’ as its estimated inhibition constant K i (i.e., the concentration required to produce half-maximum inhibition) against AChE was 0.12859 µM [58]. It is clinically relevant as patients taking canagliflozin reach a serum drug concentration of 10µM, and the brain/serum ratio of canagliflozin is 0.3. Therefore, the amount of canagliflozin penetrating the brain (3 µM) is enough to inhibit AChE [17,59]. As for other SGLT2i, the K i for inhibiting AChE is 0.177 µM for empagliflozin and 25.02 µM for dapagliflozin, and brain concentrations are 0.5 µM and 0.3 µM, respectively, so out of those two, only in the case of empagliflozin, brain concentration is enough to inhibit AChE (Table 1) [17,30,60]. Patients with Alzheimer’s disease have a reduced amount of acetylcholine neurotransmitters in the brain, and acetylcholinesterase inhibitors including donepezil, rivastigmine, galantamine are commonly used to increase the acetylcholine level and improve cognition [61]. In a rat model of cognitive impairment induced by scopolamine, canagliflozin, similarly to galantamine, decreased AChE activity, increased acetylcholine M1 receptor (M1 mAChR) and monoamines levels. It also improved cognitive functions in the Y maze task and water maze task [62]. Canagliflozin has the greatest potential of inhibiting AChE and may be a preferable solution in patients with T2DM who would also benefit from the inhibition of acetylcholinesterase.

Canagliflozin - Another Top Longevity Drug
#23

Currently I am not taking piracetam, I am only taking Noopept.
I normally buy from

They say some people get headaches of taking racetams, but I have never experienced this. Some also say racetams deplete choline and this is what causes the headaches
I tried almost everyone of the choline supplements, citicoline etc., but actually noticed no effect from any of them. Now I just take plain choline from Walmart.

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#24

Here is a side effect many may welcome.

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#25

I read many Chinese studies on Huperzine which is an acetylcholinesterase inhibitor and cognition more than 20 years ago. I have been taking Huperzine ever since. The paper that convinced me showed an effect equal to Tacrine but with fewer side effects. Here is a review on Huperzine.

“The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.”

https://www.nature.com/articles/aps20061

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#26

I worked in a neurologist’s office during graduate school doing EEG assessment and brainwave biofeedback. A woman had an orgasm, her first in years, during one of the biofeedback sessions. Jon, the doc asked excitedly, “What protocol were you using?” Unfortunately for us, it only worked for her.

#27

Might not have been the biofeedback. Maybe the technician was her type.

It is not the pistol, but the pistolero.

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#28

I’m posting my nootropics stack again. I’ve taken piracetam in the past and as it is water soluble vs phenylpiracetam which is fat soluble the effect is pretty short lived (1hr tops) . Also you need to continue taking piracetam multiple times in a day so 800mg to 1200mg 3-4 times a day. It gets pretty annoying.

Also, you probably know the TMAO related stroke risk of choline supplementation with alpha gpc or cdp choline. But, I don’t really consider it something that should be focused on because in reality most of the foods you eat contain TMAO and it can be offsetted.

Anyways,my nootropics stack:

  1. Phenylpiracetam (Nanotropil) - 100mg
  2. Vinpocetine - 10mg
  3. Mexidol (Emoxypine) - 125mg
  4. Picamillon 20mg and/or Selank
  5. Ocassionally Semax - (note: anything that increases BDNF anectodally increases hair loss (although reversable when stopped). I noticed that so I don’t take it much.)
    Highly recommend Semax 0.1 % for those with a higher risk of stroke or age related cognitive decline. For example, in Eastern europe Semax is carried on every ambulence and is admistered in the ER immediately to Stroke patients.
  6. Several eggs a day (must be pasture raised and corn and soy free) or Ocassional Alpha GPC - 300mg
  7. L-theanine - 200mg if I ever drink caffeine. I don’t tend to drink much coffee.
  8. Lithium Orotate - 1mg
  9. Have tried Zyn’s but stopped after a week. Nicotine decreases thiamine (B1) big time hence why the energy drain after it. Only way I would take Zyn’s is with large doses of thiamine.
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#29

Hi Genja,

I have been doing some research on a7 nicotinic receptor agonists searching for an effective and safe way to improve cognition via nicotinic receptors. This article is a treasure with tables of agonists and positive allosteric modulators (PAM ). The alpha 4 receptor also improves cognition.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318519/.

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#30

it sounds pretty scary, consider how many supplements contains alpha gps or choline esp. those for energy or brain focus. Are the effect dose dependent?

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#31

Exactly. dose and time dependent. Large doses (600-1200mg daily) over years. But keep in mind if you have a predisposed condition that you may or may not be aware of, your risk obviously goes up. Such as hypertension, clotting disorders etc…So it’s not for everyone, and definitely not something I would do everyday.

Eat a couple of eggs instead for the choline. Even though they have high choline levels similar to the supplements they seem not to cause the same degree of risk with TMAO as the supplements.

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#32

Participants’ plasma TMAO levels increased significantly in all 3 intervention arms containing choline bitartrate (all P < .0001), but daily ingestion of 4 large eggs (P = .28) or phosphatidylcholine supplements (P = .27) failed to increase plasma TMAO levels

People just need to give up on choline bitartrate and switch to phosphatidylcholine instead. I don’t take any of those nootropics nor am I about to anytime soon but just wanted to chime in that basically lecithin supplements are much better anyway.

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#33

Also Nefiracetam which is an Agonist for Alpha 7 nicotine receptors and also Alpha 4B.

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (α7, α4β2)

https://www.sciencedirect.com/science/article/abs/pii/S0169328X00001170

#34

I broke down my stack (the one from above) in great detail if anyone is interested. It’s a must read imo.

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#35

Huperizine is great. Didn’t have a chance to take it for an extended period of time. But will try to add it in.

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#36

I understand CDP choline does not have that stroke risk.

#37

This is good info. Thanks. I found this paper that says two interesting things:

(1) nicotine can be harmful (not what I heard from Attia), and

(2) nicotine can be harmful via over activation of autophagy. This was the first time I’ve heard that over activation of autophagy is a bad thing (even though it does make sense).

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.120.314975?download=true

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#38

Which receptors are associated with the cognitive enhancement from nnicotine?

"Recent studies have demonstrated that the α4, β2, and α7 subunits of the nicotinic acetylcholine receptor (nAChR) participate in the cognitive-enhancing effects of nicotine."0p

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#39

tfl.phd, I will now put Piracetam, Phenylpiracetam and Noopept in the category of nootropics that have no apparent effect for me. I’ve tried each of them at different times over a period of two years trying to detect something noticeable, but no, that never happened. I’ll mention the brands assuming that could have something to do with it: Intas Piracetam 400 mg tablets, Phenotropil 100 mg tablets from Cosmic Nootropic and Noopept 10 mg tablets from Cosmic Nootropic. In the case of Piracetam taking 800 mg several times a day for a week or two showed nothing. Phenotropil at 100 mg on an empty stomach (with GPC choline) before breakfast several days in a row showed nothing. Noopept 10 mg taken twice a day for several days showed nothing. I may consider doubling the dose of Phenotropil and Noopept for a future experiment, but I’m not sure. There are other things on my list that I need to try to see if there is any benefit and I hate to waste time with non-beneficial products.

Oh, just as a note, ordinary coffee or caffeine powder mixed with water is still the most beneficial nootropic I find for mental clarity and physical activity. However, Modafinil is useful at times in small amounts, but may have unpleasant hangover effects, addictive potential, and can really mess with your sleep. The small amount of 50 mg in the morning (at times when I feel the need) is just enough to be useful for me at times. With this amount it’s almost unnoticeable until I become active physically or active with other people where I notice things go more smoothly without a “wired” feeling. It’s somewhat like caffeine, but with a half-life of 10 hours or so versus caffeine’s quick downhill after 3 or 4 hours for me. I’m planning an 8 to 10 mile hike in the mountains on Labor Day. So, I’ll carry caffeine water (not coffee). But, just in case, I’ll also carry Modafinil 50 mg if I’m slowing down by 10:00 a.m. There may be a coyote and there may be a bear! So, I’ll need to be aware!

Now, for anyone who is interested, as well as Rapamycin.news, I also look here at times for possible things to try: https://www.alzdiscovery.org/cognitive-vitality/ratings . ThisYoutube site I also like: https://www.youtube.com/channel/UCb5oHt9yTBD1lJSa5rKlKfQ

1 Like
#40

I suspect your source.
I completely understand that you felt no subjective effects from piracetam or phenylpiracetam, but the noopept is a mystery unless you are an unusual non-responder.
10 mg of noopept is a rather small dose and supplement suppliers don’t always supply the amount of ingredient listed.
The problem with noopept is, from my own experience and the anecdotal reports on Reddit and other groups, it works great the first time or two but the body quickly adapts to it, then nada. Some suggest cycling it works, but it only ever worked once for me.

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#41

Interesting thanks for sharing. I cut down my stack pretty substantially recently. Piracetam in itself barely has an effect on me anymore. For me, Phenotropil 100mg seems to work quite well when i take it occasionally but it disrupts my sleep a bit even when i take i early in the morning. It just clears my mind and makes me more attentive and focused.
I also inject IM Cortexin which I started to love, and Cerebrolysin .
I also drink 5mg of Methylene blue + vit c or I just get Methylene blue + Vit C in an IV twice a week.

Interestingly coffee in itself really has no effect on me and actually causes me to be exhausted shortly after. But when I supplement with caffeine in other forms, I always take it with L-theanine to reduce jitters and that works well.

Also as an anxiolytic, I found nothing really beats L-theanine for an immediate effect.

If your taking nicotine in any form , i would supplement with large doses of thiamine given that it heavily depletes thiamine.

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