AChE-I Research

AChE-I Research
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This section has been a little slow lately, so I figured I’d share some research I posted in a few places here on a common class of nootropics to help clear up some common misconceptions.

That is, AChE-Is, like huperzine (which is in just about every nootropic) and galantamine (which is often viewed as a rarer rival to the ubiquitous huperzine)

With huperzine use, it’s often recommended to not use daily and/or to cycle it often, with the claim that the half-life was is particularly long. I’d like to discuss this purported half-life of huperzine, and reference some studies, since this is far from the first time I’ve heard this. I’ll also post some research comparing huperzine to galantamine in healthy subjects, as galantamine often seems to be touted as a superior huperzine, but, as far as simply being an AChE-I, I won’t speak to other potential benefits, I don’t think the increased cost and rarity is worth the hassle compared to huperzine, which is ubiquitous and so easy to get.

Anyway, here we go:

We often hear huperzine is touted to have a half-life of ~12 hours, likely coming from this study:

https://www.ncbi.nlm.nih.gov/m/pubmed/18348466/

Which noted a 716 minute (~12 hour) half-life, but this was with a 400mcg dose. As well see later, this is a rather high (and I’ll say unnecessary) dose, so let’s put that aside for a moment.

If you’ll excuse the poor quality of this PDF, notice that a 100mcg dose seems to have a half-life just under 5 hours:

http://www.chinaphar.com/article/download/7054/7702

As we’ll soon see, 100mcg is a more reasonable, yet still useful, dose of huperzine.

Here, 100mcg was used 2x daily in adolescent students:

http://www.chinaphar.com/article/download/7802/8893

I’m not certain how much they weighed, but a cursory search seems to put junior middle schoolers at ~51.5kg or so, give or take:

https://www.sciencedirect.com/science/article/pii/S2095254617301175

so that comes out to ~3.88mcg/kg/day, or ~272mg/day for a 70kg person, split into 2 ~136mg doses.

That all said, let’s see what 100-200mcg huperzine does in healthy subjects (and 4-8mg galantamine too while we’re at it):

https://www.ncbi.nlm.nih.gov/m/pubmed/25455867/

“Huperzine 100 μg reached peak AChE-inhibiting activity (83% of pre-drug activity) 90 min following administration…

Huperzine-200 μg reached maximal AChE-inhibiting activity 30 min post-dose (72% of pre-drug activity)…

Thereafter (starting at 150 min post-dose), both Hup-100 and Hup-200 maintained similar levels of AChE-inhibiting activity across subsequent sessions…

Galantamine also dose-dependently inhibited AChE activity…

Gal-4 reached peak inhibition (85% of pre-drug activity) at 150 min post-dose…

Gal-8 reached peak inhibition at 210 min post-dose (75% of pre-drug activity)…

With the exception of the 1330 h [3.5 h post-dose] sampling session, AChE activity in both galantamine doses was similarly inhibited… and significantly lower than Pla across all other post-drug sessions…”

So it appears that both huperzine and galantamine are effective AChE inhibitors in healthy non-elderly adults, which is nice, but:

“Despite rapid inhibition of RBC AChE (and a presumed increase in central cholinergic activity), neither huperzine A nor galantamine impacted neurobehavioral performance.”

“The lack of neurobehavioral efficacy in this study was not entirely unexpected. Our subjects consisted of healthy, non-sleep-deprived young adults. In addition, although practice effects were evident on some tasks (discussed next), in general, performance levels on all tasks were high…

Results from prior studies indicating pro-cognitive effects, taken together with our findings, indicate that in otherwise normal, healthy adults with intact central cholinergic functioning, AChE-inhibiting compounds do not exert cognition-enhancing effects. Also, the results presented here indicate that these compounds do not interfere with the normally high levels of neurobehavioral functioning seen in this cohort…”

Additionally, the study mentioned that perhaps cognitive benefits would have been noted if the tests had been more difficult/challenging. A different (rat) study noted:

“AChE activity is higher in the cerebral cortex of groups that have been trained and tested on more difficult problems than in those given easier problems. An experiment in which littermates were either trained on a difficult problem or were untrained reported that the trained rats developed significantly higher cortical AChE than their untrained littermates.”

So, we see that 100mcg and 200mcg huperzine are both effective as AChE-Is, with similar potency today 4-8mg galantamine, and that they also may be only “conditionally beneficial,” as they may only help preserve cognitive function when it’d otherwise be impaired, and/or perhaps improve cognition when presented with a more challenging task.

In summary, huperzine’s frequently touted 12 hour half life seems to be with a high 400mcg dose. A 100mcg dose seems to be closer to 5 hours. Given that 100-200mcg is an effective dose as an AChE-I, probably just stick to 200mcg/day, and frequent cycling likely isn’t as pressing of a concern as it is often claimed to be based on the 400mcg half-life. Anyway, it seems to be no more pressing of a concern than that of galantamine, which seems to poses similar AChE-I activity at 4-8mg as 100-200mcg huperzine, while itself having a half-life of 7.6 hours at 4mg and 7.2 hours at 8mg, yet I rarely see anyone mention the necessity of cycling galantamine, while it’s almost always mentioned with huperzine.

https://www.ncbi.nlm.nih.gov/m/pubmed/20156150/

Edit: more info below:

Also, there has been documented tolerance buildup to the AChE-I effects of donepezil in humans, while rodent research seems to suggest this may not be the case with huperzine, and the human studies have shown superior acute effects as well:

https://www.ncbi.nlm.nih.gov/m/pubmed/16923332/

Not to mention that, in humans, huperzine may also be superior to donepezil and galantamine to pair with memantine for treating AD (100mcg 2x daily huperzine vs 2-6mg galantamine 2x daily vs 5-10mg donepezil 1x daily):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402907/

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TL;DR:

-The ~12 hour half-life so often claimed for huperzine seems to be based on a (high) 400mcg dose

-The half-life with 100mcg seems to be closer to 5 hours

-100-200mcg huperzine seems to possess similar acute AChE-I activity as 4-8mg galantamine in healthy subjects

-4-8mg galantamine seems to have a half-life of 7-8 hours, longer than that of 100mcg huperzine

-Both huperzine and galantamine may only be conditionally beneficial for improving cognition

-Huperzine may not be subject to the same tolerance buildup that donepezil is, based on rodent research anyway

-Huperzine may be better than galantamine and donepezil when paired with memantine for treating AD

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I made a mistake in reading one study. I can admit when I screw up.

The study that I thought used ~100mcg apparently actually used 10x ~100mcg. That’s a big difference, and I’m an idiot for not catching it; looking now at the Cmax they reported relative to the other doses that were supposedly higher, that should have been a red flag. Anyway, this study that noted the ~5 hour half life used 990mcg, not 90mcg:

http://www.chinaphar.com/article/download/7054/7702

Summary of Study:

Dose: 990mcg

Half-life: ~5 hours

Cmax: 8.40 ug/L

Tmax: ~80 min

Then we have a study with 400mcg:

https://www.ncbi.nlm.nih.gov/m/pubmed/18348466/

Summary of Study:

Dose: 400mcg

Half-life: ~12 hours

Cmax: 2.59 ug/L

Tmax: ~58 min

Then we have two studies with 200mcg:

https://www.ncbi.nlm.nih.gov/m/pubmed/29058298/

Summary of Study:

Dose: 200mcg

Half-life: ~12 hours

Cmax: 1.550 ng/mL

Tmax: ~43 minutes

https://www.ncbi.nlm.nih.gov/m/pubmed/17939152/

Summary of Study:

Dose: 200mcg

Half-life: ~6 hours

Cmax: 2.47 ng/mL

Tmax: ~78 minutes

So we now have no real info on the half-life of huperzine at 100mcg, two varying half-life reports at 200mcg, one report at 400mcg, and 1 report at 990mcg.

But we do know that 200mcg huperzine reached peak AChE inhibition faster than 100mcg in the study below (72% of pre-drug activity in 30 minutes vs 83% in 90 minutes), if that helps with anything.

https://www.academia.edu/29881293/Physiological_and_neurobehavioral_effects_of_cholinesterase_inhibition_in_healthy_adults

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