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Long term effects single high dose of MDMA may have caused?

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Worried&Horrified

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Week ago when I was very drunk my friend offered me MDMA. Don't know exactly how high dose I took: he had big amount of MDMA crystals at his home. I was drunken idiot eager to redose it many times.

This was my very first (and for sure the last!) experience of MDMA. Now I've spent whole week trying to get all the information about MDMA. More research data I read, more horrified I feel. Permanent neurotoxic damage sounds awful thing to live with.

So the week has been full of anxiety, depression, hopelessness, guiltiness... But now I begin to feel normal again. My subjective feeling says my cognitive capacity, short term memory etc. are back to normal. I am a human again.

But I cannot help thinking how much unreversible damage I've done to my serotonin system: axons, dendrites etc. How bad thing one time (first time!) intoxication / high dose of MDMA is? Will my brain & mind ever be normal again?

Thank you so very much for your enlightened answers.

(I am 30+ man, 95kg)
 
Hi there. If you are getting better that is a surefire sign of recovery. It may take some time, though but don't worry, you'll be fine very likely!
First thing you have to do is GET YOUR MIND OFF OF WORRYING! The more you think of it, the worse your anxiety gets. Fact. ;)

Get well soon and don't be stupid next time, will you? :)
 
Thanks, Myr!

I fully understand I should stop thinking and get back to normal life. Past cannot be undone. But my thoughts of permanent brain damage are so annoying I cannot escape them.
 
Genuine brain damage is highly unlikely if you haven't been taking absolutely monstrous doses. All the research you read has serious flaws in the methodology that make the results useless to be able to objectively state the possibility of brain damage in normal recreational use. More than that, the amount of MDMA they had to inject to get detectable neurotoxic damage was so high I'm willing to bet normal doses don't do any permanent damage whatsoever. A whole plethora of chemicals can be neurotoxic if you ingest huge quantities, but that doesn't mean they can't be relatively harmless when used wisely. You're going to be fine, relax, you haven't fried your brain
 
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Thanks BlueBull, I really hope you are right! :) (I know MDMA is quite safe if dosage is low. The problem is I didn't knew that a week ago.)

Many research findings, for example these, are quite scary:

Single dose of MDMA causes extensive decrement of serotoninergic fibre density without blockage of the fast axonal transport in Dark Agouti rat brain and spinal cord.http://www.ncbi.nlm.nih.gov/pubmed/17359360

Long-term neuronal damage and recovery after a single dose of MDMA: expression and distribution of serotonin transporter in the rat brain
http://www.ncbi.nlm.nih.gov/pubmed/20962361

We are not rats, but many sources claim that rats can process more MDMA / kg than primates without damage. Lower amount (mg/kg) could cause equivalent damage in human brain. So if I ate 1g MDMA (which is possible) the body weight ratio is circa 10mg/kg. And my brain is...
 
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BlueBull is right. Some of those mdma studies on rats were given astronomical doses. Sounds like an experiment with an agenda. I don't have specific numbers, but purely off memory I remember there being a discussion on that in another forum (with studies quoted and other blah).

Too much of anything is bad.

I've been sticking to this site for awhile now. It's just superior, imo. :)
 
Worried&Horrified said:
Thanks BlueBull, I really hope you are right! :)

In spite of that many research findings, for example these, are quite scary:

Single dose of MDMA causes extensive decrement of serotoninergic fibre density without blockage of the fast axonal transport in Dark Agouti rat brain and spinal cord.http://www.ncbi.nlm.nih.gov/pubmed/17359360

Long-term neuronal damage and recovery after a single dose of MDMA: expression and distribution of serotonin transporter in the rat brain
http://www.ncbi.nlm.nih.gov/pubmed/20962361

We are not rats, but many sources claim that rats can process more MDMA / kg than primates. Lower amount (mg/kg) could cause equivalent damage in human brain. So if I ate 1g MDMA (which is possible) the body weight ratio is circa 10mg/kg. And my brain is...
Click to expand...
The first study injected rats with a dose of 15mg/kg. So first of all it was injected straight into the bloodstream, which is a big step up from ingesting it orally. Second of all for me, weighing 75kg, that would mean an injection of 1,2g of pure MDMA. That would probably kill me, and if it didn't it's only to expect I would have massive brain damage. That is 10x a normal recreational dose. Not an indication of possible brain damage following a normal dose of high quality MDMA at all

The second link is about the same study, it's one of the researchers that wrote a seperate paper on the same study (authors first one: Kovács GG1, Andó RD, Adori C, Kirilly E, Benedek A, Palkovits M, Bagdy G. Author second one: Kirilly E)

As for the need to scale the doses between species, could you elaborate on the sources that claim that rats can process more MDMA/kg? In any case I think I have an interesting read for you. This study talks extensively on the shortcomings of allumetric dosage scaling for MDMA in rats. Allumetric scaling is what they used to calculate the dose in the studies you linked above. It instead suggests that rats have about the same dose-response curve for MDMA as humans do, using another form of dose scaling. It talks extensively about the supposed neurotoxic properties of MDMA as well, I think you might find the conclusions interesting.

So far there hasn't been a single study done where they controlled all the relevant variables, the methodology has always been flawed in some way. There's research underway at the moment to use MDMA to treat PTSD which I hope also entails a proper study done on possible adverse effects. I read a whole lot about the subject and my opinion is that bonafide neurological damage is very unlikely when the drug is used carefully and calculated. That doesn't mean it's harmless, it might harm you in other ways, but brain damage is not one of them I think. Certainly not from a one-off too high dose. If you ever decide to try again, you never know, read a bit about it. This is a good place to start

*edit* @Kl519: yup, but it's still a discussion worth having imho. Though no matter how much we discuss it, we'll never know for sure until they get over their prejudice and research the damn chemical properly =D
 
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Erowid's MDMA Faq:

"There is solid experimental evidence that MDMA, administered in large doses and/or repeatedly, causes partial loss of serotonergic neurons in laboratory animals. Uncertain is whether this loss is permanent, reversible, or important. One study found in the rat nearly 100% recovery within a year. In another study (Ricaurte), non-human primates were dosed with MDMA and their brains were examined for morphological changes. Ricaurte found that there was no effect after 2.5 mg/kg oral doses given every two weeks, for a total of eight doses. But after a single oral dose of 5 mg/kg, he observed a 20% reduction in serotonin and its metabolite 5-HIAA, only in the thalamus & hypothalamus. There appeared to be some regrowth over time, not necessarily complete, and also some "collateral sprouting" - growth of other types of neurons in the reduced serotonin areas.

Note that in all of the animal studies, even when there are quite large serotonin system reductions (up to 90% in high MDMA dose rat studies), no behavioral deficits are observed."
 
That Ricaurte study has been rectracted. He "accidentaly" used methamphetamine instead of MDMA. Listen, the fact of the matter is we can debate this for all eternity, we'll never know for sure. Any psychoactive chemical has the potential to harm you. Caffeine has the potential to cause you a heart-attack if you ingest stupendous amounts of it over a period of time. There are indications that heavy alcohol use can produce detectable neurological damage. With all chemicals, moderation is key. But a one-off too high dose will not cause you noticeable brain damage, not any more than a one-off night of heavy binge drinking will. If that were the case we would see many many more cases of severe side-effects, with the way the most people are using the drug
 
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"But a one-off too high dose will not cause you noticeable brain damage, not any more than a one-off night of heavy binge drinking will. If that were the case we would see many many more cases of severe side-effects, with the way the most people are using the drug"

Well said. Thanks again! I truly, madly, deeply hope you're right and I haven't ruined (too many) serotonergic axons forever.
 
BlueBull-Indeed! I know I can leave the specifics to you, if you don't mind, as I see that you already have. Good stuff. :)
 
BlueBull,

I bet you're interested in this article: "MDMA-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis (2011)"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137208/

"The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction."
 
I think your friend is the one to blame more than the drug. As BlueBull pointed out, almost anything can be harmful if you use it in the wrong way.. MDMA is especially sensitive to this but if your friend had of informed you a bit better on how to take it safely you would have had a great night and woken up the next day feeling nothing more than a bit tired from having too much fun.

And I wouldn't call a week long term, I've heard many stories of people being messed up for a week or two, it just takes time for your brain to recover when you take so much but I'm sure you will be fine with just a little more time.
 
Zon, you're right: I do blame my friend. Fuck, I hate him so much right now. But after all it was me who ate all that shit. What's done is done, no matter who's the guilty one.
 
Worried&Horrified said:
BlueBull,

I bet you're interested in this article: "MDMA-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis (2011)"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137208/

"The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction."
Click to expand...
A lot of the studies referenced in that article we already discussed above. They even quote the Ricaurte study from 1988 where there were proven (in my opinion deliberate) errors made that completely falsified the results. I find that quite amusing, this article was published in 2011. Anyways I haven't read it completely, I will later on when I have some more time. But I glanced over it and from what I've read they draw the same conclusions from the same flawed research done before

Don't take this the wrong way, I mean well by saying this but I think you are looking for validation of your worries and guilt about the mistake you made. You made a mistake and it appears more frightening to you because an illegal drug is involved. Would you be so worried when you impulsively drank yourself into a serious blackout? Probably not? Well, alcohol is a proven neurotoxic substance, if you only look at the research you should be more worried about that than about a high dose of MDMA :D I'm not saying it's harmless, don't get me wrong, it's a powerful drug with potentially far-reaching consequences, neurotoxicity is far from the only thing to be worried about. But a one-off too high dose isn't going to noticeably damage your brain. If that were the case we would see young people turned into vegetables left and right. There's a whole bunch of people out there that don't know better than to roll every weekend and drop a handful of pills every time, for years on end. They get side-effects, yes, and that is to be expected, but I think accumulated neurological damage would present itself much more clearly than what we're seeing
Worried&Horrified said:
Zon, you're right: I do blame my friend. Fuck, I hate him so much right now. But after all it was me who ate all that shit. What's done is done, no matter who's the guilty one.
Click to expand...
Indeed, just chalk it up to a learning experience. You're going to be fine, and you've gained an experience. If that single occurrence makes you stop and think about it the next time you're presented with the opportunity to try a new drug then it has been a valuable experience. We live and we learn
 
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Worried&Horrified said:
BlueBull,

I bet you're interested in this article: "MDMA-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis (2011)"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137208/
Click to expand...

this paper only cites doses upwards of 10mg/kg.

in this study they show that you have the same plasma levels of MDMA and its metabolites from similar doses of mdma. so 10mg/kg would correspond to 700mg of MDMA for a 70kg person, which is equivalent to seven full doses of MDMA taken at once.


your article also agrees with the one i cited above and with this one that the way "neurotoxicity" has been measured (at those high doses >10mg/kg!) up to now isn't valid. all previous studies have looked at the levels of serotonin (5-HT), the serotonin transporter (SERT) and tryptophan hydroxylase (TPH).
the thing is: we know that MDMA due does release a lot of 5-HT using SERT and inhibits TPH (the enzyme used to synthesise serotonin). so it is clear that we will see reductions in the levels of these proteins after (heavy) mdma use. when serotonin is released it is either taken up into the synapse by SERT or degraded by MAO. since MDMA causes SERT to transport serotonin in the other direction, most serotonin will be degraded and because SERT doesn't function as it normally does, it will be flagged for destruction by the cells. the same thing happens to non-functioning TPH. but all three of these molecules/proteins are constantly degraded and rebuilt by the cells anyway, so any reduction we see here due to these mechanisms is completely reversible and that's in fact also what we see. levels of 5-HT, SERT and TPH do return to normal values within a few weeks.
in addition to that every other marker for cell death or loss of axons (in your study they used VMAT2, in others they used silver staining, .....) does not show any neurotoxicity for mdma in the range of 10-30mg/kg. proven serotonergic neurotoxins consistently give positive results with all markers.


tl;dr: there is absolutely no need to worry about serotonergic neurotoxicity.
 
I'm not sure this paper effectively rules out that serotonergic axonal/neuronal does not occur after MDMA administration. It does seem to make a lot of assumptions.

1.) How can we assume that just because there is not a glial response as seen with other selective serotonergic neurotoxins, that axonal loss is not taking place? It is conceivable that neuronal apoptotic pathways induced by MDMA may not trigger an activation of microglia or astroglial cells, as usually seen in processes such as traumatic brain injury, resulting no significant increase in GFAP expression over baseline.

2.) How can we assume that VMAT2 is equally distributed between all types of monoaminergic neurons (serotonin, dopamine, and norepinephrine) in all parts of the brain? This study looked at synaptosomes in the hippocampus (which is naturally deplete of DA axons) after pre-treating with DSP-4 to eliminate NE axons. However, if we assume that VMAT2 is not equally distributed amongst all monoamenergic neurons in the hippocampus, then it is possible you may not see a statistically significant decrease in VMAT2 after MDMA administration, even if serotonin axonotomy/fiber damage is taking place.

In addition, silver staining has low selectivity for serotonergic axons, so unless this study was sufficiently powered (which we don't know), the lack of statistically significant decrease in silver staining after MDMA may not reflect injury to serotonergic fibers, causing a Type II error.

There are newer studies that look at other radiographic markers of long tract fiber integrity such as diffusion tensor imaging and MR spectroscopy that seem to suggest that fiber integrity seems to be disrupted in various regions of subcortical white matter.

I would not hang my hat on this study that "there is absoutely no need to worry about serotnergic neurotoxicity."
 
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of course the papers i cite doesn't conclusively rule out neurotoxicity, but they show that none of the previously used methods, which led us to believe that there was serotonergic neurotoxicity in the first place are valid. so we're left with no indication for specific neurotoxic damage and therefore have no reason to assume that it occurs.

1. why should we assume that apoptosis can selectively lead to axon loss? it's a process that involves the whole cell. and the formation of apoptotic bodies (which is what we would need for loss of axons) is the last stage ocurring after chromatin condensation and karyorrhexis. also astrocytes usually play an active role in apoptotic neurdegeneration and inhibiting the activation of phagocytic cells often leads to the survival of cells destined for apoptotic cell death. it's highly unlikely that we don't see any response at all from the glial cells is there's indeed axon loss going on.

2. it doesn't have to be distrubuted equally in the absence of both dopaminergic and noradrenergic neurons. if you only have 5-ht neurons left, then the vmat2 of these neurons is all you'll measure.

the data for silver staining is consistent with experiments using fluoro-jade b. both markers only give positive results (non-specific for serotonergic neurons) for very high doses and correlated with hypterthermia rather than mdma dose.

do you have a link to those studies?


with most data pointing towards a serotonergic neurotoxicity being refuted and since we now know that interspecies scaling doesn't work as previously thought, the need to worry about it is pretty close to zero. even in the unlikely case that the reductions in 5-ht, sert and tph correlate with serotonergic axotomy in the absence of other markers for neurotoxic damage, specific serotonergic neurotoxicity is the least of your worries when you have ingested over 700mg of mdma at once.
 
bro you are fine ive rolled balls since i was 15 i am 20 now a year sober and its like i never rolled, just give it time.
 
1. I guess the point I'm trying to make here is that if MDMA is causing a structural insult to the cell, whether it be apoptosis or just loss of integrity of distal axon, it may not be invoking the same glial response as seen in, for example, traumatic injury. If MDMA is just causing distal axonotomy, is it not possible that GFAP and other glial markers will not be statistically increased over baseline, in contrast to other known serotonergic neurotoxins that may cause full blown apoptosis/cell death?

2. If VMAT2 preferentially distributes more in NE or DA axons than in 5-HT neurons, then it is possible, even with the elimination of DA or NE axons, you will have a less robust response of decrease of VMAT2 after a serotonin neurotoxin, requiring the power of the study to increase in order to compensate for that less robust response.

I will go back and try to find those studies, i believe they are from 2014 or 2013.

Finally, how to you correlate all this to the long term clinical studies? I agree most of the clinical studies are retrospective with a lot of confounding variables, but event the better designed retrospective studies and the few prospective studies (such as the NeXTC trial) seem to demonstrate long term sequelae after MDMA use. If its not axonal loss of serotonergic fibers, what do you account this findings to? Or do you believe the studies are too flawed with confounders to conclude at all that people have long term problems attributable to MDMA use?
 
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