I am talking about weekly use not day per day, because MDMA needs around 4 days to leave the human body totally. So why is it more dangerous than taking long breaks? Is it because some different transmitters such as dopamin interfere with 5-HT receptors more than usual causing toxicity? I mean logically it should react the same as taking long breaks. Well the magic effect should diminish quickly since most of the serotonin has been used before, leading to tolerance. But I don't really get how it is more toxic... Can somebody help me out?
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Why is it more dangerous to take short breaks between MDMA uses? (scientific)
- Thread starter mb-909
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Zalo
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I can't give you any references but from my understanding on MDMA neurotoxicity is that MDMA is neurotoxic to serotonergic axons and not the neuron itself. My assumption as to why possible long breaks are necessary is to give the neurons adequate time to reform new synapses. Old synapses would be lost. With repeated exposure and short breaks there will be less activity in the brain regions that rely on serotonin as a messenger because there are no serotonergic axons to send signals. You'd have to rely on 5-HTP to mediate relatively 'normal' brain activity. My best guess is that it's similar to how Parkinson's disease causes symptoms of dopamine dysregulation and L-DOPA, the precursor to dopamine, relieves some of those symptoms. Dopaminergic neurons die, which means no dopamine release to signal any neuron with dopaminergic receptors. In the case of MDMA neurotoxicity the neuron is still there but since serotonin is released at the terminal button (at the end of the axon, which is gone) it can no longer signal neurons with serotonin receptors. This leads to lowered mood, disrupted sleep, etc., which are alleviated with the use of 5-HTP. With Parkinson's the neurons are dead and regrowth of dopaminergic neurons isn't possible yet (I believe). At least with MDMA the neurons are still alive and have the potential to regrow their axons with adequate time.
This is just one idea though.
This is just one idea though.
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If the axon's die, the neuron's can't repair themselves. Therefor it doesn't matter how long your breaks are I guess... Dead is dead. The only reason I see is that it stresses out the neurons more, because you lost most of your body own antioxidants and it needs time to recover.
I suppose you should take it only a few times in life. You are going to have a better trip by taking long breaks(restored Serotonin) and don't get addicted to it. And you won't damage your system as much. There will always be damage though, you can't avoid it.
I still don't see how it is more damaging. I would say it is down regulation by the receptors. High dose's are extremly toxic and I read some studies about it, but not about the breaks....arghhhhhh....
I suppose you should take it only a few times in life. You are going to have a better trip by taking long breaks(restored Serotonin) and don't get addicted to it. And you won't damage your system as much. There will always be damage though, you can't avoid it.
I still don't see how it is more damaging. I would say it is down regulation by the receptors. High dose's are extremly toxic and I read some studies about it, but not about the breaks....arghhhhhh....
Zalo
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It had slipped my mind that the CNS can't repair itself. If axonal damage does occur in the brain then it would remain permanent. People do recover from MDMA abuse in regards to mood and such, but cognitive deficits seem long lasting based on a few studies.
Perhaps a single high dose session is really neurotoxic as it exhausts your antioxidants. Average dose repeated exposure has relatively minor neurotoxicity, but downregulated receptors and decreased levels of serotonin leads to symptoms of abuse. Average dose long breaks also has relatively minor neurotoxicity, but no downregulation of serotonin receptors with normal levels of serotonin. So you may be right about short breaks being no more neurotoxic than taking longer breaks.
Perhaps a single high dose session is really neurotoxic as it exhausts your antioxidants. Average dose repeated exposure has relatively minor neurotoxicity, but downregulated receptors and decreased levels of serotonin leads to symptoms of abuse. Average dose long breaks also has relatively minor neurotoxicity, but no downregulation of serotonin receptors with normal levels of serotonin. So you may be right about short breaks being no more neurotoxic than taking longer breaks.
Black
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neurotoxicity occurs only when the levels of HHMA exceed a certain threshold (basically the limit of your cells to detoxify reactive oxygen species; kind of like it is with a metabolite of paracemol.). recent research indicated that the threshold cannot be reached by normal recreational doses (at least those we recommend here).
the reason why you should take breaks of at least 1-3 months (depends on who you ask) long is twofold. first, your receptors (and transporters) downregulate following the huge flood of serotonin and it takes some time for that to recover. second, MDMA releases serotonin from your stores and good part of it is broken down by enzymes. serotonin biosynthesis takes a while and MDMA inhibits the slowest step in this process. so you'll have to wait for your receptors to return to normal levels as well as for your serotonin stores to fill up again.
if you dose too soon, you'll send both down again and increase the time needed for recovery. and if you do so repeatedly, you'll end up with even lower levels for even longer and this can lead to depression, anxiety, and all the other unpleasantries that come with abusing mdma.
the reason why you should take breaks of at least 1-3 months (depends on who you ask) long is twofold. first, your receptors (and transporters) downregulate following the huge flood of serotonin and it takes some time for that to recover. second, MDMA releases serotonin from your stores and good part of it is broken down by enzymes. serotonin biosynthesis takes a while and MDMA inhibits the slowest step in this process. so you'll have to wait for your receptors to return to normal levels as well as for your serotonin stores to fill up again.
if you dose too soon, you'll send both down again and increase the time needed for recovery. and if you do so repeatedly, you'll end up with even lower levels for even longer and this can lead to depression, anxiety, and all the other unpleasantries that come with abusing mdma.
@Black, is it relevant if it is a high single dose or the total repeated doses (talking about mg/kg)? I guess it is more stressing for the brain if it is single high dose. I also know that the limit should be around 1,5 mg/kg. But is there yet a certain limit where you can say it is neurotoxic?
http://ecstasy.org/info/leon.html
[FONT=arial, helvetica]"DOSE(a) EFFECT NEUROTOXICITY (based on animal data)
(mg/kg)
0.4 No observable Effect. No.
1.0 Some changes of serotonin No, probably neuromodulatory effects,
neuronal markers, among amongst which up-regulation of
which increases in serotonin serotonin system components
2.0 More long term changes in Disputed. Either neuromodulatory
predominantly decreases. effects, predominantly down-regulation
serotonin neuronal markers, of serotonin system components, or,
as some claim, the observed reductions
reflect nerve terminal degeneration.
4.0 Increased silver staining. Yes, nerve terminal degeneration.
10.0 Disappearance of serotonergic Yes, axonal degeneration.(b)
fibres and swollen and
fragmented axons.
a. Total dose taken during one day or night.
b. It is disputed whether the affected nerve terminals are serotonergic or non-serotonergic.
Comment by Dr O'Callaghan on axonal degeneration at 10 mg/kg:
This is not evidence of terminal or axonal degeneration. It is simply a loss of serotonin staining (and is accompanied by long-term, but reversible, decreases in serotonin levels). This is the example of the water in the pipe analogy I use. Serotonin is the water. If you drain the pipe you won't see staining, but that doesn't mean the pipe is not still there and functioning. I still maintain (and so would Ricaurte and Molliver) that the d-fen story is relevant to the MDMA story. I argue that this supports the lack of evidence of neurotoxicity, although Ricaurte and Molliver will say they all produce damage.
Comment on the above comment by Leon van Aerts:
Besides this point of lack of serotonin antibody staining observed by Wilson et al. (1989), Ricaurte et al. (1988b) and O'Hearn et al. (1988), these researchers found that axons were swollen and fragmented. These are clear-cut signs of neurodegenerative processes. I therefore do not see how such signs cannot be regarded as signs of axonal degeneration. Furthermore, the reversibility of the effects is only partial after such high doses, as was observed by Fisher et al. (1995), Lew et al. (1996), Sabol et al. (1996) and Ricaurte et al. (1992).
The estimates that are produced by these extrapolations are summarized in Table 1. However, it should be noted that, for several reasons, the levels of exposure associated with certain events are only rough estimates. One reason is that for the interspecies extrapolation, standard extrapolation factors related to body weight have been used. However, when new data on the pharmacokinetics of MDMA in animal and human emerge, more precise extrapolation factors can be derived, so that the exposure levels associated with certain events may be adjusted up or downward.
Furthermore, average responses in animals were extrapolated to the human. However, the sensitivity of both animals and humans varies between individuals. Therefore, susceptible individuals may exhibit nerve terminal degeneration at lower levels of exposure than the average. Finally, the more severe effects were observed in animals that were exposed to repeated high doses of MDMA. No attempt was made to investigate these effects at lower doses. It is reasonable to expect that at somewhat lower doses these effects also would have occurred, albeit to a lesser extent.
Also, the occurrence of reduced serotonin and 5-HIAA levels, as well as reduced densities of serotonin uptake sites observed long after the administration of MDMA, are interpreted by some investigators as signs of nerve terminal degeneration, and therefore as signs of neurotoxicity, whereas others claim that these effects are only of a modulatory nature.
In any case, when looking at an undisputed marker of neural damage p; increased silver staining p; it seems reasonable to suppose that at a total dose of 4 mg/kg MDMA neurotoxicity in the form of nerve terminal degeneration may occur in humans. This is a dose that is frequently consumed by the more heavy users during a day or night.
It may be argued that if serotonergic damage has occurred in more heavy users it is strange that so little clinical evidence has emerged. A possible explanation for this could be the apparent redundancy of the serotonergic system. Even when a large proportion of the serotonergic nerve terminals has been destroyed basal functionality may be preserved. Kirby et al. (1995) showed that more than 95% of tissue serotonin levels had to be depleted before extracellular levels were reduced. How much the serotonergic system in humans can be depleted before a loss of function is observed, or under which circumstances a reduced capacity would become apparent, is unknown.
Until now neural damage as a result of MDMA use has not been shown in humans. Also is it unclear what the functional consequences would be when serotonergic brain damage would occur in humans. Nevertheless the animal data do give reason for concern. Therefore, for the time being, it may be advisable to refrain from the use of high doses, boosters or bingeing of Ecstasy.[/FONT]"
http://ecstasy.org/info/leon.html
[FONT=arial, helvetica]"DOSE(a) EFFECT NEUROTOXICITY (based on animal data)
(mg/kg)
0.4 No observable Effect. No.
1.0 Some changes of serotonin No, probably neuromodulatory effects,
neuronal markers, among amongst which up-regulation of
which increases in serotonin serotonin system components
2.0 More long term changes in Disputed. Either neuromodulatory
predominantly decreases. effects, predominantly down-regulation
serotonin neuronal markers, of serotonin system components, or,
as some claim, the observed reductions
reflect nerve terminal degeneration.
4.0 Increased silver staining. Yes, nerve terminal degeneration.
10.0 Disappearance of serotonergic Yes, axonal degeneration.(b)
fibres and swollen and
fragmented axons.
a. Total dose taken during one day or night.
b. It is disputed whether the affected nerve terminals are serotonergic or non-serotonergic.
Comment by Dr O'Callaghan on axonal degeneration at 10 mg/kg:
This is not evidence of terminal or axonal degeneration. It is simply a loss of serotonin staining (and is accompanied by long-term, but reversible, decreases in serotonin levels). This is the example of the water in the pipe analogy I use. Serotonin is the water. If you drain the pipe you won't see staining, but that doesn't mean the pipe is not still there and functioning. I still maintain (and so would Ricaurte and Molliver) that the d-fen story is relevant to the MDMA story. I argue that this supports the lack of evidence of neurotoxicity, although Ricaurte and Molliver will say they all produce damage.
Comment on the above comment by Leon van Aerts:
Besides this point of lack of serotonin antibody staining observed by Wilson et al. (1989), Ricaurte et al. (1988b) and O'Hearn et al. (1988), these researchers found that axons were swollen and fragmented. These are clear-cut signs of neurodegenerative processes. I therefore do not see how such signs cannot be regarded as signs of axonal degeneration. Furthermore, the reversibility of the effects is only partial after such high doses, as was observed by Fisher et al. (1995), Lew et al. (1996), Sabol et al. (1996) and Ricaurte et al. (1992).
The estimates that are produced by these extrapolations are summarized in Table 1. However, it should be noted that, for several reasons, the levels of exposure associated with certain events are only rough estimates. One reason is that for the interspecies extrapolation, standard extrapolation factors related to body weight have been used. However, when new data on the pharmacokinetics of MDMA in animal and human emerge, more precise extrapolation factors can be derived, so that the exposure levels associated with certain events may be adjusted up or downward.
Furthermore, average responses in animals were extrapolated to the human. However, the sensitivity of both animals and humans varies between individuals. Therefore, susceptible individuals may exhibit nerve terminal degeneration at lower levels of exposure than the average. Finally, the more severe effects were observed in animals that were exposed to repeated high doses of MDMA. No attempt was made to investigate these effects at lower doses. It is reasonable to expect that at somewhat lower doses these effects also would have occurred, albeit to a lesser extent.
Also, the occurrence of reduced serotonin and 5-HIAA levels, as well as reduced densities of serotonin uptake sites observed long after the administration of MDMA, are interpreted by some investigators as signs of nerve terminal degeneration, and therefore as signs of neurotoxicity, whereas others claim that these effects are only of a modulatory nature.
In any case, when looking at an undisputed marker of neural damage p; increased silver staining p; it seems reasonable to suppose that at a total dose of 4 mg/kg MDMA neurotoxicity in the form of nerve terminal degeneration may occur in humans. This is a dose that is frequently consumed by the more heavy users during a day or night.
It may be argued that if serotonergic damage has occurred in more heavy users it is strange that so little clinical evidence has emerged. A possible explanation for this could be the apparent redundancy of the serotonergic system. Even when a large proportion of the serotonergic nerve terminals has been destroyed basal functionality may be preserved. Kirby et al. (1995) showed that more than 95% of tissue serotonin levels had to be depleted before extracellular levels were reduced. How much the serotonergic system in humans can be depleted before a loss of function is observed, or under which circumstances a reduced capacity would become apparent, is unknown.
Until now neural damage as a result of MDMA use has not been shown in humans. Also is it unclear what the functional consequences would be when serotonergic brain damage would occur in humans. Nevertheless the animal data do give reason for concern. Therefore, for the time being, it may be advisable to refrain from the use of high doses, boosters or bingeing of Ecstasy.[/FONT]"
Black
Bluelighter
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- Nov 26, 2004
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do you mean repeated doses with days in between or repeated doses in the course of a night? if the former, then taking a low dose even protects from damage that would occur with huge doses afterwards. if the latter, then we simply have no data for that. we'd need more human pharmacokinetics studies to say for sure how the levels change with repeated dosing. my guess would be that for such a scenario, with mdma's autoinhibition of the relevant cytochromes, that we'd see a larger percentage excreted unchanged (which is a good thing) in the urine...
there's no limit where we can say it's neurotoxic in humans. neurotoxicity has never been observed in humans and i'm not even sure if the specific serotonergic neurotoxicity does even occur at any dose. the best marker for neurotoxicity is silver staining and in your article (which btw uses an outdated scaling method to estimate the effects of doses in humans - they see 40mg/kg in the rat as equal to 4mg/kg in humans; that is not surprising given the article's age) it correctly says that silver staining in the rat occurs at doses starting at 40mg/kg in an unspecific way. so this is not due to serotonergic neurotoxity (probably hyperthermia?). the models which show clear serotonergic neurotoxicity are all monkey models and we now know that these monkeys produce a lot more hmma than we do.
I mean repeated doses in one night. It is said that a recreational dose is around 250-300 mg one session. A single 200 mg dose is more toxic than 300 mg split over the night?
So even if I dose like a single oral dose of like 3 mg/kg it doesn't neccesarly mean that any brain damage occured? As far as I know we do not have the technology to actually tell if something is really permanently damaged or not. And everybody acts differently.
My anxienty keeps me going since I have not really known for sure how much MDMA was contained in the pills I took. It is just a worst case scenario.
So even if I dose like a single oral dose of like 3 mg/kg it doesn't neccesarly mean that any brain damage occured? As far as I know we do not have the technology to actually tell if something is really permanently damaged or not. And everybody acts differently.
My anxienty keeps me going since I have not really known for sure how much MDMA was contained in the pills I took. It is just a worst case scenario.
I found something about a single dose vs repeated low doses:
http://link.springer.com/article/10.1007/s00213-012-2894-7?LI=true#
The HMMA results are much lower by repeated use's than by a single dose.
http://link.springer.com/article/10.1007/s00213-012-2894-7?LI=true#
The HMMA results are much lower by repeated use's than by a single dose.
Here is a review (pdf) saying that HMMA is not able to pass the brain blood barrier and therefor it is not part of the resulting 5-HT depletion.
http://www.google.de/url?sa=t&rct=j...dr7Vm4_4AEbqRJQ&bvm=bv.78677474,d.ZWU&cad=rja
http://www.google.de/url?sa=t&rct=j...dr7Vm4_4AEbqRJQ&bvm=bv.78677474,d.ZWU&cad=rja
Black
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- Nov 26, 2004
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- 2,884
^^ nice find.
well, that hhma and hmma aren't responsible for serotonin depletion is obvious. we know that mdma releases a lot of serotonin and inhibits tryptophan hydroxylase for weeks. they didn't measure any parameter that specifically measures neurotoxicity. we know that depletion of serotonin doesn't mean death of neurons or axons.
they say that, while measuring serotonin levels right afterwards doesn't say anything about cell death, measuring serotonin levels after a week is related to cell death (well, obviously it's related: if you kill serotonergic neurons they won't make any serotonin, but that doesn't mean that if you have decreased serotonin then the neurons are dead. and especially when you know that the drug you're giving inhibits serotonin synthesis for such a time span, it's misleading. when you then posit that it means neurotoxicity (like in the abstact) it's a complete non sequitur. "related" is an often used word in publications when you don't know exactly how it works or when you want your hypothesis to sound more credible than it actually is...).
so unless they actually test with markers that are suitable for assessing neurotoxicity, this tells us nothing we don't already know.
that they found no detectable levels of hhma and hmma in the brain, while very unexpected, isn't too surprising in the light of no specific serotonergic neurotoxicity occuring in rats. i would however be surprised if they didn't find those metabolites in the brains of squirrel monkeys or baboons, where this sort of damage actually happens.
i don't know if someone already pointed it out to you, but this paper has some excellent data on the topic (including why serotonin depletion doesn't mean neurotoxicity in the case of mdma). if ricaurte and his collegues had read it, they would have saved themselves a lot of work with the one you cite above.
well, that hhma and hmma aren't responsible for serotonin depletion is obvious. we know that mdma releases a lot of serotonin and inhibits tryptophan hydroxylase for weeks. they didn't measure any parameter that specifically measures neurotoxicity. we know that depletion of serotonin doesn't mean death of neurons or axons.
they say that, while measuring serotonin levels right afterwards doesn't say anything about cell death, measuring serotonin levels after a week is related to cell death (well, obviously it's related: if you kill serotonergic neurons they won't make any serotonin, but that doesn't mean that if you have decreased serotonin then the neurons are dead. and especially when you know that the drug you're giving inhibits serotonin synthesis for such a time span, it's misleading. when you then posit that it means neurotoxicity (like in the abstact) it's a complete non sequitur. "related" is an often used word in publications when you don't know exactly how it works or when you want your hypothesis to sound more credible than it actually is...).
so unless they actually test with markers that are suitable for assessing neurotoxicity, this tells us nothing we don't already know.
that they found no detectable levels of hhma and hmma in the brain, while very unexpected, isn't too surprising in the light of no specific serotonergic neurotoxicity occuring in rats. i would however be surprised if they didn't find those metabolites in the brains of squirrel monkeys or baboons, where this sort of damage actually happens.
i don't know if someone already pointed it out to you, but this paper has some excellent data on the topic (including why serotonin depletion doesn't mean neurotoxicity in the case of mdma). if ricaurte and his collegues had read it, they would have saved themselves a lot of work with the one you cite above.