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Huperzine A, warning?


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#31

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Posted 04 November 2004 - 07:35 AM

I agree with nootropi.

bdnf you may think this is common knowledge among neuroscience circles but you can't expect omniscience from your fellow forum members. Be a bit more gracious and explain concisely why things work the way you say they do.

Cheers.
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#32

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Posted 04 November 2004 - 07:38 AM

Also if you're interested bdnf, drop my thread and give your input about transcranial direct current stimulation. I'd like to hear some input from someone who seems to have formal education in neuroscience.

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#33 killer_macro

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Posted 04 November 2004 - 08:01 AM

It is not respectful to make unsubstantiated claims here.

Why don't you just look it up? If he were to put the references here it would just take up space. More specifically, a HELL of a lot of space (because there is SO much info on this).

#34 nootropi

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Posted 04 November 2004 - 03:54 PM

Why don't you just look it up?  If he were to put the references here it would just take up space.  More specifically, a HELL of a lot of space (because there is SO much info on this).


Huh? Take up space? I never knew that we were short on space!

This is not a personal issue; it is a custom in this forum to cite relevant sources for claims.

If no source is included the claim is classified as anecdotal, or theoretical. This is not a basis for drawing a conclusion.

#35 Mike M

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Posted 04 November 2004 - 07:06 PM

A friend of mine took 900mcg of Huperzine to see what would happen. He had insaine cold shivers, nightmares unlike anything he had seen and quite a bit of nausea. Realize, he knew something like this would happen and was only curious what would happen.

Anyone else seen a Huperzine overdose?

#36 killer_macro

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Posted 04 November 2004 - 08:13 PM

This is not a personal issue

Yes it is. Just admit you are wrong and shut up. Adam, you always argue about the most trivial things.

#37 bdnf

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Posted 04 November 2004 - 08:32 PM

If you require references for basic neuroscience facts, then anything else I have to say in this forum will be far too advanced for you. I'm not going to waste my time providing references when this is essentially common knowledge among those who have at least some education in neurophysiology. And if it is not, there is an exhaustive collection of papers on the internet for those that feel the need to confirm my ‘anecdotes’, ‘claims’ and ‘theoretical’ discourse.

I do not want to listen to Nootropi’s whining any further, nor do I want to disobey the apparent ‘custom’ in this forum. Thus, I will no longer visit this forum, but rather I will seek individuals with which I can hold a more intellectual discussion without this childish bickering.

Nootropi, do not reply, because I will not return. I just hope that the several different chemicals which you ingest (from a business providing them in ziploc bags!) helps you to enhance cognitive function, even if you decided upon such a stack based on a limited (or, as it seems, unexistent) understanding of your nervous system.

Edited by bdnf, 04 November 2004 - 08:48 PM.


#38

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Posted 04 November 2004 - 08:44 PM

A friend of mine took 900mcg of Huperzine to see what would happen.  He had insaine cold shivers, nightmares unlike anything he had seen and quite a bit of nausea.  Realize, he knew something like this would happen and was only curious what would happen.

Anyone else seen a Huperzine overdose?


Uhhh... why did he do that? Just for the hell of it?

I experience an increase in imagination, visualization, and in particular dreams/nightmares (more often nightmares) when using HupA. My ceiling for using Huperzine is 300mcg, at that point I experience more uncomfortable side effects.

#39 unipolar_mania

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Posted 04 November 2004 - 09:02 PM

*Clap clap* Nootropi.

Stop acting like you run this forum and speaking like you know everyone here. There are probably lots of people here that do know what bdnf is saying (e.g. velocidex). I enjoyed reading what bdnf was saying...it was very interesting. Great work in causing him to leave.

Edited by unipolar_mania, 04 November 2004 - 10:13 PM.


#40

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Posted 04 November 2004 - 09:07 PM

Nootropi, do not reply, because I will not return.


That's too bad, even when there are disagreements I value each educated response in this forum.

#41 nootropi

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Posted 05 November 2004 - 01:48 AM

You guys are so heated. And what about? Just because I ask you to not spew unscientific data here?

Okay; let me be clear:

I never said I knew everybody from this forum. I do know several members personally, though.

I can assure you that I do not know unipolar mania, bdnf, or velocidex.

For your information, the only reason I mention that I do know several members personally is to offer my friendship to anybody in this forum who cares about and respects its members. I take this community personally. What I mean is that I care about this forum and its members.

When I make a claim, I assume that it may be possible that someone may make a choice based on my reasoning. I would hope this choice would not be later considered ill advised in the absense of conclusive supporting evidence. Therefore whenever I make a claim, I present evidence that justfies my reasoning. ;)

So all of the sudden I am the "bad guy" because I question your reasoning? That makes no sense. Okay: maybe in your world it does. The world in which I live is full of misinformation; therefore those of us who are rational cite the sources of our reasoning. Theoretics are great; they surely are interesting and can lead to other developments, but they are no basis for drawing a conclusion.

But please do not offer medical advice or reasoning here without a scientific citation. If you are not already familar with the pubmed database, please familarize yourself with it.

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.


Thank you very much.

Be well.

Edited by nootropi, 05 November 2004 - 02:03 AM.


#42 unipolar_mania

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Posted 05 November 2004 - 02:05 AM

When I make a claim, I assume that it may be possible that someone may make a choice based on my reasoning.

Pity help that person.

#43 nootropi

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Posted 05 November 2004 - 02:08 AM

Pity help that person.


Exactly! Alas! We have a clear representation of my point of emphasis!

Pity help that person. What are you saying?

Pity help the person who relies on scientic reasoning to make a claim?

I will gladly accept your definition of pity. Anyday. Please pity me. [thumb]

I accept and learn from several member's advice and recommendations. I have learned a lot from:

(In order of appearance): Life Mirage, Cosmos, rizzer, AORsupport, spongled, lynx, ejdavis1, Zen Catholic, scottl, lemon, dopamine, pinballwizard...to name a few...hey, even bdnf has contributed a lot to scientific discussions here...

#44 unipolar_mania

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Posted 05 November 2004 - 02:19 AM

I pity the person who takes your advice. Why would someone take the advice of some weird, argumentative, over enthusiastic nootropic user with near to no education in pharmacology or neuroscience. Makes perfect sense to me.

#45 nootropi

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Posted 05 November 2004 - 03:09 AM

I pity the person who takes your advice.  Why would someone take the advice of some weird, argumentative, over enthusiastic nootropic user with near to no education in pharmacology or neuroscience.  Makes perfect sense to me.


I don't think I need a degree in pharmacology nor neuroscience to understand the terminology or mechanims discussed in medical literature, nor do several other members. It just takes a little evaluation, integration, and intelligence (and time)!

Maybe not you...but that's not your fault...you just need some more noootropics!

Be well.

#46 dopamine

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Posted 05 November 2004 - 08:13 PM

I have been using Huperzine A for about 5 months now relatively consistently at a dose of 50 mcg/day. A couple of days ago my supply ran out, and I have been postponing buying more, so I figured I would see what effects abruptly withdrawing the drug from my system would do. All in all, I feel a little less "sharp" and my short-term memory seems to be somewhat weakoned, whereas on Huperzine it was very sharp. I'm on about the 3rd day now, and a lot of the symptoms are beginning to subside, with the aid of large doses of choline supplements (CDP Choline, Alpha GPC primarily) and Piracetam.

So I think that some downregulation of acetylcholine receptors does take place when inhibiting acetylcholine esterase over a prolonged period of time, however the recovery rate of this effect is relatively quick depending on the extent of downregulation (i.e. how long the AchE inhibitor has been taken and in what dose). These drugs do have great applications, such as alternative treatment for ADD, senile dementia, etc. If this class of drugs does in fact downregulate acetylcholine receptors, I think that would be viewed, in the context of treating a mental illness, as an acceptable side effect relative to the potential benefit.

Just a personal observation. Some of you may want to try not taking whatever acetylcholine esterase inhibitor you are taking to see what effects it may have (if any). It is possible that these drugs work best on cycles, in which during the withdrawl period your brain is able to re-compensate for the downregulation of ACh receptors.
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#47 dalessm

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Posted 09 November 2004 - 06:24 PM

If this class of drugs does in fact downregulate acetylcholine receptors, I think that would be viewed, in the context of treating a mental illness, as an acceptable side effect relative to the potential benefit.


Hi Dopamine,

Ok...I'm confused. Doesn't this side effect of long term Hup A usage (downregulation) nullify the very reason for taking Hup A (maintenance of high synaptic acteylcholine levels)?

If your goal is to decrease acetylcholine breakdown, but your brain is overcompensating for increased acetylcholine levels by shutting down acetylcholine receptors, what is the point?

#48 dopamine

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Posted 09 November 2004 - 07:07 PM

Hi Dopamine,

Ok...I'm confused. Doesn't this side effect of long term Hup A usage (downregulation) nullify the very reason for taking Hup A (maintenance of high synaptic acteylcholine levels)?

If your goal is to decrease acetylcholine breakdown, but your brain is overcompensating for increased acetylcholine levels by shutting down acetylcholine receptors, what is the point?


Increasing acetylcholine levels in the synaptic cleft can theoretically increase short-term memory and/or long-term memory consolidation. If acetylcholine is broken down too rapidly by acetylcholine esterase, and you have a large number of receptors, memory consolidation would be much more impaired than if you had fewer receptors but a higher amplitude of cholinergic neurotransmission (measured as a function of time the acetylcholine molecule has to stimulate a post-synaptic response). The same happens with SSRI's, in which the 5-HT2a receptor is heavily downregulated over a long period of time (and has been offered as a hypothesis for the body composition side-effects of this class of drugs).

When there are low levels of any given neurotransmitter (as measured by post-synatpic response time) the CNS compensates with an increased number (or density) of the corresponding receptors to try and achieve the same outcome as a fewer number would with an apt degree of neurotranmission. With this increase, however, comes a loss of efficiency and a increase in the time for which a post-synaptic response is elicited. Basically, with a increase in receptors with a low level of neurotransmission, the sum of the impulses (a + b + c + d) will equal the total charge (Te) needed to elicit the proper response (i.e. to increase calcium influx into a neuron). However, when fewer receptors exist but with twice the potential for post-synaptic charge, in our theoretical example only a+b (two receptors) would be needed to equal the total charge Te. When fewer receptors are needed, less coordination among them is necessary to produce a sum total current and thus increases the efficiency of the neurotransmission.

However, when no deficiency of acetylcholine exists within the given number of acetylcholine receptors, downregulation can result in a small number of receptors receiving excessive amounts of stimulation, which can (when the neuron "misfires") cause overstimulation of the receptor and can either desensitive it to post-synaptic responses or flood a neuron with excessive levels of calcium. This is relatively unlikely to happen with Huperzine, as it has been shown to be neuroprotective against NMDA-induced neurotoxicity; however, there is a possibility for overstimulating the AMPA receptors. There is a careful balance we must strike when using smart drugs/nootropics that affect these systems of the brain.
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#49 dopamine

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Posted 09 November 2004 - 08:49 PM

Someone mentioned they wanted proof that downregulation occurs as a result of increased post-synaptic stimulation of receptors. Here's what I could find (in the time span of about 10 minutes):

Neurochem Int. 2001 Jun;38(7):573-9.
Cortical 5-HT(1A) receptor downregulation by antidepressants in rat brain.

Srinivas BN, Subhash MN, Vinod KY.

Department of Neurochemistry, National Institute of Mental Health and Neurosciences, P.B. No. 2900, Bangalore 560 029, India.

Total 5-HT binding sites and 5-HT(1A) receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt) and clomipramine (10 mg/kg body wt), for 40 days, using [3H]5-HT and [3H]8-OH-DPAT, respectively. It was observed that chronic exposure to tricyclic antidepressants (TCAs) results in significant downregulation of total [3H]5-HT binding sites in cortex (42-76%) and hippocampus (35-67%). The 5-HT(1A) receptor density was, however, decreased significantly (32-60%) only in cortex with all the three drugs. Interestingly, in hippocampus imipramine treatment increased the 5-HT(1A) receptor density (14%). The affinity of [3H]8-OH-DPAT was increased only with imipramine treatment both in cortex and hippocampus. The affinity of [3H]5-HT to 5-HT binding sites in cortex was increased with imipramine treatment and decreased with desipramine and clomipramine treatment. 5-HT sensitive adenylyl cyclase (AC) activity was significantly increased in cortex with imipramine (72%) and clomipramine (17%) treatment, whereas in hippocampus only imipramine treatment significantly increased AC activity (50%). In conclusion, chronic treatment with TCAs results in downregulation of cortical 5-HT(1A) receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT(1A) receptors in the mechanism of action of TCAs.



Med Hypotheses. 2004;63(6):1047-50.
Dopamine receptor downregulation: an alternative strategy for schizophrenia treatment.

Tsai SJ.

Department of Psychiatry, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, No. 201 Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan, ROC.

Schizophrenia is a common and devastating illness. The cause of schizophrenia is still unknown and the simplest formulation of the "Dopamine hypothesis" posits that schizophrenia results from dopaminergic hyperactivity. Under the hypothesis of dopaminergic hyperactivity in schizophrenia, antipsychotics blocking the dopamine D2 receptor (DRD2) and other approaches to reduce dopamine (DA) transmission have been used to treat schizophrenia. I propose that dopamine receptor (DR) downregulation could be an alternative strategy to compromise dopaminergic overactivity implicated in the pathogenesis of schizophrenia. Agonist-induced receptor downregulation includes receptor proteolysis, modulation of receptor gene transcription and affecting of RNA stability. These processes cause a decrease of existing receptors and reduction of receptor synthesis. This hypothesis could explain the antipsychotic mechanisms of DA agonists or partial agonists, like aripiprazole. It is suggested that the development of agents that increase DR downregulation could be an alternative strategy for schizophrenia treatment.


Pharmacotherapy of stimulant dependence: one of Japan's greatest public health challenges.

McCance-Katz E, Sevarino K, Gottschalk PC, Kosten T.

Stimulant dependence has become a major public health problem in the world over the last 15 years, and pharmacotherapies have been evolved based on our understanding of the neurobiological alterations induced by these drugs. Among the stimulants cocaine and amphetamine are the most common dependencies, and they share several common pathophysiologies in producing disease and in guiding medication approaches to treatment--neurotransmitter re-normalization, reversal of cerebral perfusion abnormalities and peripheral cocaine blockers. First is neurotransmitter re-normalization. A relative catecholamine deficiency occurs following prolonged abuse of cocaine and amphetamine due to transporter upregulation and receptor downregulation. This abnormality in dopamine and serotonin neurotransmission appears to be associated with depression and has supported antidepressant treatments to re-normalize neurotransmission. Dopaminergic and serotonergic agonists have also been given to re-normalize neurotransmission, but in contrast to substitution therapies such as methadone, LAAM or buprenorphine for opioids, these approaches have had limited success in unselected cocaine dependent patients. As a correlary approach to substitution, however, aspects of dopamine function can be augmented by dopamine beta hydroxylase inhibitors such as disulfiram to increase the aversive properties of stimulants and decrease their abuse. The second medication approach relates to cerebral perfusion defects and associated cognitive deficits due to vasoconstriction and abnormalities in platelets, which can respond to antiplatelet therapies as well as excitatory amino acid (EAA) antagonists. These EAA antagonists can prevent neuronal damage that is due to the release of EAA during cerebral ischemia induced by stimulant use. Finally, peripheral blockade treatment for cocaine may be possible using a newly developed active vaccine that blocks the uptake of cocaine from the bloodstream into the brain. Its potential efficacy has been shown in rodents that decrease their self-administration of cocaine when immunized with this vaccine, and preliminary human studies support its safety and immunogenicity. In summary, stimulant pharmacotherapy has made great progress in developing treatments based on understanding the neurobiology of these abused drugs, but these pharmacotherapies must be delivered in the context of appropriate behavioral and cognitive psychotherapies, which are also rapidly evolving.


Effect of chronic treatment with 5-hydroxytryptophan on cortical serotonin receptors in the rat.

Pranzatelli MR.

Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, New York.

L-5-Hydroxytryptophan (5-HTP) is a clinically useful antimyoclonic drug that is thought to act at serotonin (5-HT) receptors after decarboxylation to 5-HT. However, the chronic effects of 5-HTP on central 5-HT receptors and the activity of 5-HTP at 5-HT receptor subtypes have not been previously reported. In rats treated 28 but not 7 consecutive days with high doses of 5-HTP (50-200 mg/kg), cortical 5-HT2 (-20%) and 5-HT1 (-11%) sites were downregulated without altered receptor affinity, but only the changes in 5-HT2 sites were significant. In naive frontal cortex in vitro, however, 5-HTP and 5-HT were more active at 5-HT1 sites, and 5-HTP was inactive at 5-HT2 sites. The differential effects of high-dose 5-HTP on 5-HT receptors suggest that 5-HT2 receptor downregulation may be relevant either to the antimyoclonic effect of chronic 5-HTP therapy in posthypoxic myoclonus or to development of tolerance.


Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice.

Li B, Duysen EG, Volpicelli-Daley LA, Levey AI, Lockridge O.

Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Acetylcholinesterase (AChE) hydrolyzes acetylcholine to terminate cholinergic neurotransmission. Overstimulation of cholinergic receptors by excess acetylcholine is known to be lethal. However, AChE knockout mice live to adulthood, although they have weak muscles, do not eat solid food, and die early from seizures. We wanted to know what compensatory factors allowed these mice to survive. We had previously shown that their butyrylcholinesterase activity was normal and had not increased. In this report, we tested the hypothesis that AChE-/- mice adapted to the absence of AChE by downregulating cholinergic receptors. Receptor downregulation is expected to reduce sensitivity to agonists and to increase sensitivity to antagonists. Physiological response to the muscarinic agonists, oxotremorine (OXO) and pilocarpine, showed that AChE-/- mice were resistant to OXO-induced hypothermia, tremor, salivation, and analgesia, and to pilocarpine-induced seizures. AChE+/- mice had an intermediate response. The muscarinic receptor binding sites measured with [3H]quinuclinyl benzilate, as well as the protein levels of M1, M2, and M4 receptors measured with specific antibodies on Western blots, were reduced to be approximately 50% in AChE-/- brain. However, mRNA levels for muscarinic receptors were unchanged. These results indicate that one adaptation to the absence of AChE is downregulation of muscarinic receptors, thus reducing response to cholinergic stimulation.



#50 nootropi

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Posted 09 November 2004 - 09:02 PM

..."the results indicate"...I always liked that saying...one I like even more is "we conclude."

We are familar with the age associated "downregulation" of the human cholinergic system. There may be also be an assocation with "too much" acetylcholine. But the human cholinergic is far more complex than the rat or the mouse. The brains of those respective animals may serve as models for what may occur in the human.

Thank you for providing us with those references; we need more folks like you around here, dopamine. Thanks for sharing with us. [thumb]

#51 dalessm

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Posted 09 November 2004 - 10:34 PM

However, when no deficiency of acetylcholine exists within the given number of acetylcholine receptors, downregulation can result in a small number of receptors receiving excessive amounts of stimulation, which can (when the neuron "misfires") cause overstimulation of the receptor and can either desensitive it to post-synaptic responses or flood a neuron with excessive levels of calcium. This is relatively unlikely to happen with Huperzine, as it has been shown to be neuroprotective against NMDA-induced neurotoxicity; however, there is a possibility for overstimulating the AMPA receptors.


Thanks so much for your extensive knowledge and thoughtful response!

I'm curious though...What would one experience cognitively in the case of overstimulation of NMDA or AMPA receptors? For example, lack of concentration/racing thoughts?

#52 unipolar_mania

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Posted 09 November 2004 - 11:24 PM

Thanks so much for your extensive knowledge and thoughtful response!

I'm curious though...What would one experience cognitively in the case of overstimulation of NMDA or AMPA receptors? For example, lack of concentration/racing thoughts?


Monosodium Glutamate (MSG) is an NMDA receptor agonist. Thus, if you were to take a substantial amount of MSG you would know what NMDA overstimulation feels like.

NMDA and AMPA receptor overstimulation is going to amplify the effects of glutamate, the excitatory neurotransmitter. Too much glutamate transmission --> increases the noise-to-signal ratio in the brain ('noise' = resting activity of neurons; 'signal' = a neuron which is active, i.e. generating action potentials) --> fuzzy thoughts. You are also likely to experience anxiety and perhaps a headache. Oh, and if you are a smoker or have other addictions, increased glutamate activity in the nucleus accembens will intensifies cravings.

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#53 velocidex

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Posted 11 November 2004 - 11:44 AM

Go to pubmed, type in downregulation and look at the plethora of information that emerges.

I dont do neurochem; i'm a physics and law student. As such I don't have on hand any neuropharmacology textbooks from which I could cite references. I'l go see if I can find one.




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