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Health - Huperzine A - Nootropic or "acetylcholinesterase inhibiting neurotoxin?"

Discussion in 'Nootropics' started by Synesthesiac, Nov 16, 2010.

  1. Synesthesiac

    Synesthesiac R.I.P. Palladium Member

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    Ok there seem to be many good things written about this. For example (from this site)

    And there's other information about it elsewhere:

    But, I stumbled across this snippet from another forum online and was unsure whether it was a valid criticism or not.

    http://brainmeta.com/forum/index.php?showtopic=13949&view=findpost&p=108083
    Scare tactics? Or valid point?
     
    Last edited by a moderator: Apr 30, 2017
  2. sambocyn

    sambocyn Newbie

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    mostly scare tactics, but something worth looking into...

    "ACHe is there for a reason. Inhibiting ACHe long term will basically give you mild brain damage, roughly equatable with excitotoxicity of high glutamate/NMDA doses, seratonin syndrome (or any toxic accumulation of molecules as a byproduct of inhibited metabolism)."

    um, no. citations?

    "Ok, NMDA isn't an "experimental neurotoxin"".

    yes it is. the NMDA receptor is a glutamate receptor subtype that selectively responds to the synthetic excitoxin. (wikipedia NMDA#Biological_function)

    "Huperzine A is an NMDA antagonist."

    interesting.

    "The brain upregulates NMDA receptors in response to its antagonism, but this is not a good thing. Huperzine A will, over time, increase NMDA desensitization and kill your ability to learn information."

    these two statements are inconsistent, i think.

    "Huperzine A is most likely not safe long term. Ache inhibitors are potent neurotoxins."

    not all are. many are therapeutic, like huperzine a. (wikipedia AChEI#Examples)
     
  3. dae141

    dae141 Newbie

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    There is a saying: "the dose makes the poison" and it is probably relevant here. Just because inactivating huge amounts of the brain's ACHe is bad doesn't mean doing so for a small amount is necessarily very dangerous.
     
  4. Impure157

    Impure157 Silver Member

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    As I have been taking Huperzine A as a treatment for an autoimmune disorder I have, moderate cases of which are treated with acetylcholinerase inhibitors, I've been researching it fairly extensively. With that said, the mechanism described by sambocyn in the quote above is something that can occur in various pathways in the brain. I understand how it seems contradictory but it's been shown that in response to excessive antagonists binding to certain receptor sites there will be an increase in the concentration of the receptors at that site. This causes the brain to become desensitized to whatever will bind to the receptors at that site, as the increased receptor concentration means more of what activates them will be required to produce a response. Usually this increase can be reversed by abstaining from whatever the antagonist was, but after long periods of upregulation at those sites that may not be the case.

    P.S. I know this has been proven to occur at a few receptor sites (such as the NMDA receptors or the D2 dopamine receptors) from various drugs and psychological disorders, but where else this can occur in the brain I have no idea.
     
  5. joefear

    joefear Silver Member

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    So what about Rivastigmine?
    Does anyone have any experiences with this?
     
  6. Shampoo

    Shampoo entity of sorts Staff Member

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    For what it's worth, the concerns regarding Huperzine A as an NMDA-antagonist are likely irrelevant. Most individuals dose Huperzine at 200-500µg, which should produce a plasma concentration of well below 0.05µM. The IC50 for NMDA antagonism is >45µM. Any dose which would cause Huperzine A to act as an NMDA antagonist would cause a slew of side-effects related to excessive ACh well before that.

    As for Huperzine A as a potential neurotoxin, this is going to be dose-related - any AChEI will cause some neurotoxicity at large doses. Considering that the plasma concentration required for effective AChE-inhibition could be achieved by an oral dose of 50µg, I think keeping doses in a reasonable range would reduce the probability of neurotoxicity to about zero - though, obviously with the lack of studies in healthy human volunteers, this is all speculation.
     
  7. sambocyn

    sambocyn Newbie

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    citation?


    if what i know of neuropharm is right, IC50 is a property of drugs, not receptors.

    IC50 measures the toxicity of a drug. NMDA antagonism is the effect, the molecule is the cause. if Huperzine A were a very potent NMDA antagonist, it could have a very low IC50.

    saying not to worry on that reason doesn't seem safe.
     
  8. DiabolicScheme

    DiabolicScheme Titanium Member

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    Is actually sounds like a possibility when you consider down-regulation/up-regulation happens to other receptors in the brain.

    However, take antipsychotics for instance; if used for a short period to blockade dopamine wouldn't the brain up-regulate dopamine and if this were the case wouldn't antipsychotics be a novel substance to reverse amphetamine tolerance?

    What I'm getting at is that I don't believe every receptor responds with up regulation; I'll have to do some more reading about the functioning of the NMDA receptor.

    If this is the case this means things like DXM would also increase the likely hood of brain damage with regular use.
     
  9. Shampoo

    Shampoo entity of sorts Staff Member

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    Wang XD et al, 1999. Modulation of NMDA receptor by huperzine A in rat cerebral cortex. Or Zhang JM & Hu GY, 2001 (they found a higher IC50).
    Correct, IC50 is a basic pharmacological term which identified the concentration of a drug necessary to exhibit half-maximal inhibition in vitro. It is often used as a starting point for identifying in vivo concentrations.
    IC50 has nothing inherently to do with the toxicity of a drug. It is a measure of effectiveness, not toxicity. Huperzine A is not a potent NMDA antagonist, that was the whole point.
    The point is that the concentrations at which it can act as an AChE inhibitor are much lower than those where it begins to impact NMDAR function directly. So the doses for these two effects are far apart, and achieving the latter (NMDA antagonism) would mean being at hundreds of times the necessary dose for AChE inhibition, which would present far more problems than the NMDA antagonism.
    All receptors can respond with up- or downregulation in response to inhibition/excitation, respectively. Presynaptic release mechanisms can also be altered in response to excessive inhibition/excitation. This is standard across biological signaling machinery.
    Potentially, sure - but you would have to be targeting the same subtype of dopamine receptors, of which there are many.
    NMDA receptors do upregulate in response to antagonists. This is well established. The point is that the NMDA-receptor antagonist effects of huperzine happen at such high concentrations that to achieve NMDA antagonism would be to far exceed the dose that would maximally inhibit AChE, which would be far more damaging.
    DXM induces modest upregulation in both NMDA and D2 dopamine receptors.
     
    Last edited: Jul 8, 2013