MDMA Folklore

[vecktor]

There is a dutch longditudinal study from a couple of years ago showing cognitive impairment and higher incidence of depression amongst 'ecstacy' users (I am careful to use the term ecstacy not MDMA because the users were using street pills) compared to a matched population

Unfortunately this study appears to be methodologically pretty solid.

The real world implications of long term ecstacy use are less clear, moderate use does not seem to be a significant problem.
if MDMA was a damaging as the rodent studies suggest then the E generation who are now in their 40's should be mentally sluggish depressed zombies, on the whole they are not, though it might go some way to explain the popularity of certain TV programmes.

 

[Hammilton]

Like anything else, different people--you and I for example--obviously respond to MDMA in wildly different ways. If it makes you feel like that, then of course your antipathy for the drug is personally well justified based on your experiences with it just as my enthusiasm for it was personally well justified based on my own experiences with it.

However, mdma science has made more than one outrageous claim over the years, and believe me, I have been following this story closely for decades: for example, at one point it was being claimed that a single standard sized recreational dose of mdma caused Parkinson's in humans and at another point in time they were promoting the idea that mdma, and again I'm not making this up, causes actual holes in one's brain. Not surprisingly, many people believed these claims and probably still do to this day. Yeah, that irks me. Maybe it shouldn't, but it does. I'll try to work on that, I guess.

For a drug to be considered truly neurotoxic, though, something bad--reallly bad--should happen after you take it. This is obviously true for something like MPTP, but 99% of the time, it's simply not true for something like MDMA, and that's a fact.

You're upset because you've never gotten information about science through an appropriate publication. It's obvious, because those claims were never published. Re: Holes- this was a reference to 'dead' spots in PET scans. This absolutey happens.

It's so obvious that you've never read a single journal when you keep bringing up nonsense like this. The news media sensationalizes all sorts of things, most much worse than drugs. Bringing up scientifically irrelevant science like Ricaurte's 2002 Science paper and out of context "holes" and parkinson's is hilarious, because if you had, you'd know what the actual evidence for them is.

I'd suggest reading all of these:

Ecstasy use-Parkinson's disease link tenuous.
Jerome L, Doblin R, Mithoefer M.
Mov Disord. 2004 Nov;19(11):1386. No abstract available.
PMID: 15389978 [PubMed - indexed for MEDLINE]


Rapidly progressive parkinsonism in a self-reported user of ecstasy and other drugs.
O'Suilleabhain P, Giller C.
Mov Disord. 2003 Nov;18(11):1378-81.
PMID: 14639685 [PubMed - indexed for MEDLINE]

What is the evidence that Ecstasy (MDMA) can cause Parkinson's disease?
Kish SJ.
Mov Disord. 2003 Nov;18(11):1219-23. Review. No abstract available.
PMID: 14639660 [PubMed - indexed for MEDLINE]


The reality of psychomotor problems, and the possibility of Parkinson's disorder, in some recreational ecstasy/MDMA users: a rejoinder to Sumnall et al. (2003).
Parrott AC, Rodgers J, Buchanan T, Scholey AB, Heffernan T, Ling J.
Psychopharmacology (Berl). 2004 Jan;171(2):231-3. Epub 2003 Nov 21. No abstract available.
PMID: 14634710 [PubMed - indexed for MEDLINE]

Response to: Parrott AC, Buchanan T, Heffernan TM, Scholey A, Ling J, Rodgers J (2003) Parkinson's disorder, psychomotor problems and dopaminergic neurotoxicity in recreational ecstasy/MDMA users. Psychopharmacology 167(4):449-450.
Sumnall HR, Jerome L, Doblin R, Mithoefer MC.
Psychopharmacology (Berl). 2004 Jan;171(2):229-30. Epub 2003 Nov 21. No abstract available.
PMID: 14634709 [PubMed - indexed for MEDLINE]


3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.
Iravani MM, Jackson MJ, Kuoppamäki M, Smith LA, Jenner P.
J Neurosci. 2003 Oct 8;23(27):9107-15.
PMID: 14534244 [PubMed - indexed for MEDLINE]

Take a look at the case studies out there from people who used MDMA only. Unfortunately they're the best we'll get, since giving people the high dose chronic MDMA that causes these problems is more than a little unethical.

 

[Hammilton]

There is a dutch longditudinal study from a couple of years ago showing cognitive impairment and higher incidence of depression amongst 'ecstacy' users (I am careful to use the term ecstacy not MDMA because the users were using street pills) compared to a matched population

Unfortunately this study appears to be methodologically pretty solid.

The real world implications of long term ecstacy use are less clear, moderate use does not seem to be a significant problem.
if MDMA was a damaging as the rodent studies suggest then the E generation who are now in their 40's should be mentally sluggish depressed zombies, on the whole they are not, though it might go some way to explain the popularity of certain TV programmes.

Right, one the whole moderate use doesn't seem to be a major problem. Heavy usage is quite different though, and there are certainly severe deficits seen in many of the heavier users.

 

[shibireru]

... they were promoting the idea that mdma, and again I'm not making this up, causes actual holes in one's brain.

Certain NMDA antagonists produce brain vacuolization, at least in rats. Since certain 5-HT receptors appear to modulate glutamatergic neurotransmission, I don't actually find the idea to be at all preposterous.

 

[nuke]

Take a look at the case studies out there from people who used MDMA only. Unfortunately they're the best we'll get, since giving people the high dose chronic MDMA that causes these problems is more than a little unethical.

The users who develop dyskinesias from MDMA are few and far inbetween. I knew a user who consumed well over 1000 pills and hundreds of mgs IV'd in sessions over the course of a few hours and they had have not developed any sort of movement disorder. Even look at Ann Shulgin; she used ecstasy regularly at doses over 200mg and she seems to be doing okay. These sorts of dyskinesias are caused by dopaminergic toxicity which MDMA only has in animals at very high doses. Since dyskinesias occur regularly in the population not using drugs it's also difficult to tell if the MDMA has anything to do with it aside from incidental timing.

From one of the studies you selected (Kish SJ: What is the evidence that Ecstasy (MDMA)...):

In this regard, the O’Suilleabhain and Giller investi-
gation, which was subjected to an intensive review
process in this journal, stands in contrast to the two
previous (Letter to the Editor) case reports, which did
not even acknowledge the theoretical possibility that the
Ecstasy exposure and parkinsonism might have been
coincidental, that no proof had been obtained that the
patients had ever used Ecstasy or, in the case of the most
recent report, that previous neuroimaging investigations
found no evidence of striatal dopaminergic damage in
human Ecstasy users. Clearly, a much tighter external
peer-review process needs to be employed before publi-
cation of such anecdotal case reports.

I recall an epidemiology study where regular old amphetamine was correlated to an increased risk of Parkinson's disease, though..

 

[Rectify]

Hammilton,

I'm sorry I was such a dick to you yesterday. Some kind of odd, vaguely powerful, negative, spiritual force which I can't fully explain or describe came over me yesterday while I was posting.

Thank you for pointing out which journal articles I should check out next are. Unfortunately, mdma neurotoxicity is among the least of my worries at this point, but I will gladly check them out if and when I have the opportunity.

 

[Sturnam]

For a drug to be considered truly neurotoxic, though, something bad--reallly bad--should happen after you take it.

I think you're confusing neurotoxicity with observable, behavioral changes. Neurotoxicity does NOT equal behavioral/mental changes. Neurotoxicity is a progressive scale. At the low end of the spectrum, little or no changes are observed. At the opposite end, severe movement/mental impairment/death result.

Take for example the progression of Creutzfeldt–Jakob disease (mad cow disease equivalent in humans). For the first period of infection, there are measurable (can be see through a microscope of brain biopsy) damages to the brain tissue. Yet, the infected individual has absolutely NO symptoms. Then, as the disease progresses, the behavioral changes rapidly increase.

Also, we can compare this to ED50's (effective dose for 50% of test subjects). There is a critical point where effects from a drug (or neurotoxicity) are noticed. Below that threshold, the drug still exists in the body, but is not in concentration strong enough to elicit a response.

 

[PsychedelicPeptide]

It is true that I haven't looked at the scientific literature with respect to MDMA in several years, not since I was in college to be precise

Could you please inform us of what stage you were at in college when you "looked at the literature?"

 

[Rectify]

The first time was in 1995. I was a sophomore.

 

[Hammilton]

Well that explains the huge holes in your knowledge on the subject.

 

[melange]

I would classify permanent reduction in 5-ht uptake sites "neurotoxic."

 

[Riemann Zeta]

^^ Not necessarily. Well, first off, let me say that it is highly doubtful that a couple of MDMA experiences results in a permanent reduction in plasma-membrane localized SERTs in humans. But nonetheless, check out this paper in J. Neurochem:

Callaghan et al (2007). In vivo analysis of serotonin clearance in rat hippocampus reveals that repeated administration of p-methoxyamphetamine (PMA), but not 3,4-methylenedioxymethamphetamine (MDMA), leads to long-lasting deficits in serotonin transporter function. J Neurochem. 100: 617-627.

The gist of the study was to determine the effect of PMA and MDMA administration on in vitro measures that have been called "neurodegeneration;" that is, serotonin (5-HT) uptake, 5-HT transporter (SERT) density and 5-HT content in the hippocampus, and compare with effects on in vivo 5-HT clearance.

From the abstract: Male rats received PMA, MDMA (4 or 15 mg/kg s.c., twice daily) or vehicle for 4 days and 2 weeks later indices of SERT function were measured. [(3)H]5-HT uptake into synaptosomes and [(3)H]cyanoimipramine binding to the SERT were significantly reduced by both PMA and MDMA treatments (ed: indicating the infamous downregulation of cell surface localized SERTs). In contrast, clearance of locally applied 5-HT measured in vivo by chronoamperometry was only reduced in rats treated with 15 mg/kg PMA.

So the observation that 5-HT clearance in vivo was unaltered by even this ridiculously huge MDMA treatment regiment (in rats, a species that really reacts poorly to amphetamines) suggests that in vitro measures like reductions in plasmalemmal SERT radioligand binding don't completely predict the functional state of serotonergic uptake in vivo. Seems to me (and the authors) like there might be a compensatory mechanism at work (at least in the wake of MDMAergic toxicity). The study also confirms what many people already suspected: PMA is some nasty shit.

 

[Rectify]

I've always heard bad things about para-methoxyamphetamine [PMA] too, but interestingly, some of those same people who called PMA a "crappy ecstasy type drug" raved on and on about 3-X-PMA, where X=Cl, Br, or I, saying that aromatic halogenation of PMA led to a highly visual, true psychedelic of the very best sort.

Naturally, no one else seemed to believe them. I really don't know either way and probably never will.

 

[filenet]

i hate a mate who loved PMA....then his parents turned off the life support

 

[Sturnam]

I've always heard bad things about para-methoxyamphetamine [PMA] too, but interestingly, some of those same people who called PMA a "crappy ecstasy type drug" raved on and on about 3-X-PMA, where X=Cl, Br, or I, saying that aromatic halogenation of PMA led to a highly visual, true psychedelic of the very best sort.

Naturally, no one else seemed to believe them. I really don't know either way and probably never will.

Not to get off topic much, but there's actually a report or 2 on here about a guy who tried PMEA (para-methoxyethylamphetamine). the first time he was totally blown away, but so far it seems like no one has re-created that experience. not to mention that lots of people are scared because of how close it is to PMA.

 

[filenet]

wasn't PMA Shulgin's first ever substance experience? things could have been a little different if he fried himself that night

 

[inverse_agonist]

In line with Riemann Zeta's post, something else to consider is the effect of antidepressant drugs on SERT expression, serotonin clearance, etc.

Abstract of PMID 12151556:

Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.

I'm not comfortable with the way the term "neurotoxicity" gets thrown around with respect to MDMA, either. MDMA is not toxic to serotonin neurons the way that, say, 5,7-dihydroxytryptamine is toxic to them. If a reduction in 5-HT reuptake sites is neurotoxic, then it follows that widely prescribed antidepressants are neurotoxic. It would also suggest that the antidepressant potential of MDMA should be receive attention, given this overlapping effect with drugs known to be effective. Common sense tells us that these aren't reasonable conclusions.

In Parkinson's disease, I believe something like 80% of the striatum's dopamine has to be lost before motor symptoms appear. Like Sturnam said, neurotoxicity is not the same thing as functional significance. As far as the functional significance of MDMA exposure is concerned, it would seem that it produces some memory impairments, which should be interpreted cautiously because of polydrug exposure and particularly cannabis exposure.

(I admit I don't follow the MDMA literature closely, though)

How does MDMA "neurotoxicity" compare to the danger of, say, hearing loss from clubbing regularly?

 

[Hammilton]

MDMA reduces 5HT receptor densities. SSRIs down regulate SERT. huge difference.

What 5,7-DHT does is much more related to MDMA than either to SSRIs. I don't understand the relevance of the example.

 

[nuke]

Pick up a book! http://books.google.ca/books?id=5QfL19H5nVkC

5,7-DHT does not reduce 5HT2 receptor density as they are post-synaptic and does not even reduce 5HT1A receptor density.
MDMA enhances 5HT1A receptor density. MDMA at low doses does not effect 5HT2A/C receptor density except in the olfactory cortex.
Antidepressants downregulate 5HT2 receptors.
Agonists and antagonists cause internalization of 5HT2 receptors.

 

[inverse_agonist]

My reason for bringing up SERT is to question the validity of SERT binding as a measure of neurotoxicity. Serotonin terminals express SERT. MDMA exposure reduces SERT density. This is often interpreted as "neurotoxicity," since the underlying assumption is that lower levels of SERT imply fewer terminals.

SSRIs cause similar reductions in SERT, but these are never taken to be evidence of neurotoxicity. These reductions in SERT expression are not accompanied by memory problems, depression, or other risks of MDMA.

If MDMA is neurotoxic, the evidence for this must be something other than SERT expression. 5,7-DHT is frequently used to kill serotonin neurons outright. That, to me, unambiguously falls within the scope of "neurotoxicity."

Abstract of PMID 16541247:

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. OBJECTIVE: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of "interspecies scaling" to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. RESULTS: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1-2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10-20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. CONCLUSIONS: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.

In the same way that nicotine can have beneficial effects on cognition without "growing brain cells," MDMA can be bad for you without being a "neurotoxin." Because so much research is funded by the US government, including agencies with names like the "National Institute on Drug Abuse," I think it's fair to ask whether the continued use of the term "neurotoxicity" is a bit disingenuous. If one wishes to discuss the effects of MDMA on SERT or receptor density, or 5-HT levels, or whatever, one can do so without using a term that misleadingly implies that cell death is occurring.

I'm just making a semantic piont, but I don't think suspicions of disingenuousness are unwarranted, considering NIDA's use of the image linked below, and the fact that it led to the "ecstasy puts holes in your brain" urban legend. The government would never encourage the spread of disinformation about drugs, would they?

http://www.erowid.org/chemicals/show_image.php?i=mdma/mdma_nida_brainscans1.gif