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(MDMA) Loss of Magic = Loss of Neurons? (or, How to Prevent MDMA Neurotoxicity)

Does anyone have ideas as to why Piracetam and other -racetams bring back the magic (for some)?

I find this most interesting because they so no affinity at all for serotonin or dopamine.
 
Montecarlonos said:
Does anyone have ideas as to why Piracetam and other -racetams bring back the magic (for some)?

I find this most interesting because they so no affinity at all for serotonin or dopamine.
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From Wikipedia:
The mechanism of action of piracetam, as with racetams in general, is not fully understood, but it influences neuronal and vascular functions and influences cognitive function without acting as a sedative or a stimulant.[3] It is hypothesized to act on ion channels or ion carriers[citation needed], thus leading to non-specific increased neuron excitability, while explaining its lack of agonistic or inhibitory effect on synaptic action (quite unlike most neurotransmitters), and its low toxicity.[13] It has been found to increase blood flow and oxygen consumption in parts of the brain but this may be a side effect of increased brain activity rather than a primary effect or mechanism of action for the drug.[14]

Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors which are implicated in memory processes.[15] Furthermore, Piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability.[15][16] Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).[13] It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brain.[17][18]
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If you look at the link to the research paper I linked to, you'll notice that there's a whole section linking neurotoxicity (axon degeneration?) to activation of NMDA receptors by glutamate. Perhaps this is involved in some way.

I don't know. I think it's hard to know since we don't know exactly how Piracetam works.
 
thelearner said:
From Wikipedia:

If you look at the link to the research paper I linked to, you'll notice that there's a whole section linking neurotoxicity (axon degeneration?) to activation of NMDA receptors by glutamate. Perhaps this is involved in some way.

I don't know. I think it's hard to know since we don't know exactly how Piracetam works.
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Interesting. Doing a quick google scholar search shows that NDMA antagonists inhibit neurodegeneration associated with MDMA exposure. Piracetam isn't a antagonist per se but blocks most of the effects of dissociates, which NDMA antagonist also do.

So piracetam might lead some interesting research in regards to neurotoxicity in combination with MDMA considering it's a neuromodulator.
 
Piracetam is positive modulator of NMDA, not a real agonist but kinda does the opposite of NMDA antagonism, hance it blocks ket and other dissociatives.

Stress hormones upregulate some serotonine receptors, piracetam increases the main stress hormone of rats, a hypothesis is that it upregulates serotonine receptors this way.
My own theory is that it just increases the effects of agonists somehow, since it appears to potentiate, stimulants, empathogens, psychedelics and gabaergics, and receptors dont rapidly upregulate (eg just coadministration is enough for the enhancement in effects).

The reason NMDA antagonists protect against damage is mostly because most are A7 antagonists, and A7 plays a major role in monoamine efflux, eg they inhibit the drug from working (initially).
 
MeDieViL said:
Stress hormones upregulate some serotonine receptors, piracetam increases the main stress hormone of rats, a hypothesis is that it upregulates serotonine receptors this way.
My own theory is that it just increases the effects of agonists somehow, since it appears to potentiate, stimulants, empathogens, psychedelics and gabaergics, and receptors dont rapidly upregulate (eg just coadministration is enough for the enhancement in effects).

The reason NMDA antagonists protect against damage is mostly because most are A7 antagonists, and A7 plays a major role in monoamine efflux, eg they inhibit the drug from working (initially).
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Wouldn't that make piracetam an anti-depressive? With the upregulation of serotonin?

Do you have more info on A7 receptors/antagonists? A quick google/wikipedia didn't return much.
 
Montecarlonos said:
Wouldn't that make piracetam an anti-depressive? With the upregulation of serotonin?

Do you have more info on A7 receptors/antagonists? A quick google/wikipedia didn't return much.
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1. No piracetam modulates NMDA and acetylcholine, but are associated with depression, and thus piracetam can induce depression in some individuals.

2.
Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.
Chipana C, Torres I, Camarasa J, Pubill D, Escubedo E.

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Joan XXIII s/n, Zona Universitaria Pedralbes, 08028 Barcelona, Spain.
Abstract
We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.
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Memantine prevents MDMA-induced neurotoxicity.
Chipana C, Camarasa J, Pubill D, Escubedo E.

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
Abstract
MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes. In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR. In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [(3)H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24h and 7 days after treatment. MDMA induced a significant reduction in [(3)H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM. Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an increase in basal acetylcholine release should also be taken into account.
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Forgive my lack of understanding of the cholinergic system here. I'm trying to follow what's being said here, but just a bit unclear how all of these systems tie together.

Is it possible that Piracetam potentiates MDMA through a mechanism that also increases toxicity, like hyperthermia causing a stronger release of 5-HT and DA?

atara: I've been wanting to try Ketamine. Now I have the excuse I need! How absolutely brilliant that a common combination could potentially be neuroprotective.
 
No, piracetam will likely protect against toxiticy due to its antioxidant activity, nmda agonism or antagonism has little influence on monoamine efflux in normal doses.

There's no evidence that ketamine protects against MDMA toxiticy.
 
atara said:
Ketamine is a nicotinic antagonist.
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They work because they block amp and mdma from working, ket is highly synergetic with MDMA, in other words its A7 antagonism isnt strong enough to prevent toxiticy.
 
atara said:
So it's yet another Prozac?

Meh.
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?
No ket works amazing with other drugs and is a great drug, it wont help toxiticy tough, but who gives a shit, we aint snorting line's of ket for toxiticy are we?;) speaking of ket it goes great with a low dose of AMT%)
 
MeDieViL said:
?
No ket works amazing with other drugs and is a great drug, it wont help toxiticy tough, but who gives a shit, we aint snorting line's of ket for toxiticy are we?;) speaking of ket it goes great with a low dose of AMT%)
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I meant memantine is yet another prozac, i.e. stops MDMA neurotoxicity but can't be used effectively for that purpose.

Ketamine is awesome.
 
Yes, memantine wont help with toxiticy (it will initially inhibit amphetamine and MDMA and other drugs, during the "memantine adaptation phase" after that A7 upregulates and all drugs work again (with neurotoxiticy, altough NMDA antagonism reduces some amp toxiticy itself, but most is mediated by oxidative stress).

Memantine is an excellent agent for tolerance tough, read my thread on NMDA antagonists and tolerance:
http://www.bluelight.ru/vb/showthread.php?t=501875
 
IMO mdma does not kill serotonin neurons but it does prune dendrite off the cell body. This is important because they affect the RELEASE of serotonin in the body. Without proper dendrites the cell will not be functional. Dendrites can regrow but not the way they are suppose to leading to bad things.

The loss of magic is likely more a result of the loss of dendrites coupled with receptor downregulation. I would say for light users it has more to do with receptor downregulation and for heavy users it is actual dendrite loss causing a permanent loss of magic. Hence why light users can reclaim the magic and heavy users usually can not.
 
bben: Agreed 100%.

MeDieViL said:
Yes, memantine wont help with toxiticy (it will initially inhibit amphetamine and MDMA and other drugs, during the "memantine adaptation phase" after that A7 upregulates and all drugs work again (with neurotoxiticy, altough NMDA antagonism reduces some amp toxiticy itself, but most is mediated by oxidative stress).

Memantine is an excellent agent for tolerance tough, read my thread on NMDA antagonists and tolerance:
http://www.bluelight.ru/vb/showthread.php?t=501875
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Very interesting stuff. Would this apply to MDMA as well? Seems like it would (excluding, of course, this thread's theory that axon / dendrite loss = loss of magic!) I see some discussion of Amp, but didn't have time to read entire thread / links. Hopefully you can shed some light.

Does this mean taking DXM with MDMA would potentiate the dose as with Amp? Safety concerns?
 
Also, is it possible that part of why Ketamine is so widely enjoyed with MDMA is that it boosts the effects of already circulating MDMA and metabolites in addition to its own psychoactive effects?
 
thelearner said:
bben: Agreed 100%.


Very interesting stuff. Would this apply to MDMA as well? Seems like it would (excluding, of course, this thread's theory that axon / dendrite loss = loss of magic!) I see some discussion of Amp, but didn't have time to read entire thread / links. Hopefully you can shed some light.

Does this mean taking DXM with MDMA would potentiate the dose as with Amp? Safety concerns?
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NMDA antagonists upregulate 5HT1A, i dont have any data on the other serotonine receptors, so its questionable wheter memantine can work against mdma tolerance, it works against amp tolerance because nmda antagonists upregulate D2 and D3.

DXM with MDMA is dangerous, ket is just a good drug, it likely doesnt do anything against tolerance, its too short acting and ive never seen anyone succesfully using ket for amp tolerance or something, only succes reports on DXM and memantine.

St johns worth upregulates several serotonine receptors, but it cant be used with MDMA, NMDA antagonists could have an advantage over that, i'm on 40mg memantine, so far i cant give you any anecdotal experience on mdma tolerance as i havent been hammering it lately, so its theoretical.

Also keep in mind NMDA antaogonists generally block or slow tolerance from building up, but they dont really reverse it, they do tend up to speed up recovery when taking a break.
 
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