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real and perceived danger of responsible MDMA usage

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nintey

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I am looking for someone to talk to me about just how dangerous MDMA is when taken at 120 mg range with a possible 50 mg redose about an hour in.

I recently read this article that was released this past year stating that mdma was found to induce irreversible neuronal damage resulting in memory loss, depression and impulsiveness.
http://www.scribd.com/doc/180210336/Taurah-et-al-2013-pdf

While I am a biology major I am looking for someone to tell me if this article is a bit exaggerated or if mdma is not possible to be used in even a responsible measure without causing damage.

Thank you for anyone that takes the time to help me with this question
 
What's with the redactions? They seem to have been chosen with care. For instance, this is redacted:

Therefore, while there is good evidence that the neurotoxicity of MDMA causes long-lasting compensatory alterations in specific brain regions of animals, there is insufficient evidence that related effects occur in humans. However, as the acute behavioral and pharmacological effects...
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(parts shown in blue are redacted)

However, a major problem with previous human ecstasy research is a failure to use adequate control groups to control for polydrug use in ecstasy users. Arguably, the psychological deficits attributed to ecstasy use could be caused by the consumption of other recreational drugs, including alcohol, amphetamine, cannabis, cocaine, heroin, and ketamine, either alone or in combination with ecstasy.
Click to expand...

Et cetera. There are many more redactions of this sort in the linked paper, and they seem to have been chosen to obscure the parts of the article which indicate the limitations of the study. At the least, this indicates that the person who sent you the redacted paper may not be trustworthy.

The major problem I see with the study is this -- they don't stratify participants based on source! They state that participants in different groups responded to different advertisements -- some from newspaper advertisements, some from their friends, some from websites, and some from drug treatment centers. It does not seem like a huge leap to suggest that those who were referred by friends might have somewhat different backgrounds than those referred by clinics! The goal of the authors seems to have been to build a large sample size, and they were successful, but they may have compromised the quality of their data. The fact that their results differ quite significantly from other studies suggests this. The authors state:

The large effects in our study compared with previous studies may be because our participants tended to be older and because we used a very strict "knowledge of effects" criterion for inclusion in the ecstasy groups. An additional or alternative reason may be that our sample was biased towardsusers who were already experiencing drug-related health prob-lems. However, this bias is an unlikely explanation for the greater impairment in our findings compared with other reports because most other studies have also used opportunity samples recruited online, via posters in nightclubs, or advertisements in newspapers
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Am I convinced? Not really. There are two problems with this.

First, it doesn't matter if you recruit participants from the Internet -- as long as they all come from the Internet. If your ecstasy users come from the Internet and your nondrug users come from the local bridge club, that's a confounding factor. This isn't seen in studies where everyone is from the Internet. Perhaps they've really discovered that online fora cause sleep disturbances (it's 3 AM as I post this). In this study, it sounds like many of the ecstasy users were from an online forum (bluelight?) while many of the others were from newspaper advertisements and friendly referrals. Unfortunately the article does not clearly explain which users were primarily recruited to the study from which source!

So why don't they stratify? Well, that would destroy the large sample size they spent four years building. It's a shame. Science is hard.

Second, the "very strict 'knowledge of effects' criteria" may exclude a large number of legitimate ecstasy users and therefore bias the sample. For example, depressed ex-ecstasy users might wistfully remember MDMA's profound euphoria more strongly than non-depressed ex-users. Sometimes "knowledge" is really "shared opinion", too; if "knowledge of effects" includes, for example, "this drug made me depressed", well, y'know.

It's rare that a study on a well-trodden topic will upturn scientists' understanding of the topic a great deal. This study seems to be part of the rule, not the exception.
 
I'm a biology student as well and spend qutie some time flipping through journals on this subject. I don't think there is a general consensus on the harmfulness of MDMA in humans within the scientific community. What we do know with certainty is that it causes long-lasting nerve damage in various animal models, especially with higer and repeated doses. Human studies are harder to perform and not suffer from some sort of bias. Some of the one's I have read have found that current and former ecstacy (ab)users are more likely to develop depression and anxiety issues, one study also showed a mild memory/learning impairment in former users compared to control group. It's hard to say with a definite yes or no: MDMA is bad.

From my readings I've concluded that MDMA is most definitely not something I consider "safe" and should not be done at high amounts or even semi-frequently. A few times (<4) a year at total doses below 200mg would be unlikely to cause long-lasting detrimental effects in my opinion.
 
The evidence that MDMA damages neurons is not strong even in animals. Over the years there has been a strong political bias in funding and hence conclusions of research and grant proposals. Most the studies use ridiculously high doses which are irrelevant to real whole situations and even still the most they ever really show is that serotonin receptors, transporters and enzymes are down-regulated which is no surprise given the strong serotonin release. If anything it would be odd if it didn't down regulate them. I know of no studies that show reliable evidence for this particularly in relevant doses.

The only study I know of that bothered to actually label SERT using GFP rather than using radio labeled binding found SERT to be internalised and degraded following MDMA exposure with no loss of actual neurons. Using the methods most papers use they would have found a reduction of neurons based on this SERT down regulation because it would have shown a lot weaker binding on the cell surface hence fewer cells have been strong enough to be counted. They are right in that if the neurons were gone they would see the same thing but they ignore the fact that the more logical and expected down regulation of SERT and serotonin receptors and enzymes would also give the same result using those tests.

The reality is that if you write a grant proposal or submit a paper that says 'drugs are bad' your way more likely to be accepted than if you say 'no significant damage found'.
 
I don't think publication bias is a good enough reason to discard the large amount of literature on MDMA's toxic effects out there. Simply browsing around on this (and other drug related forums) you'll find plenty of MDMA abusers complaining about memory deficits and other cognigtive and mood problems who I doubt were funded by the government. Heavy users I have known in my own personal life also most certainly suffer from memory problems and bouts of depression frequently.

There's a good recent review I found this morning covering MDMA use in humans:
Aims: This paper aimed to review how scientific knowledge about the human psychobiology of MDMA has developed over time.
Methods: In this paper, the empirical findings from earlier and later studies will be reviewed.
Results: When MDMA was a ‘novel psychoactive substance’, it was not seen as a drug of abuse, as it displayed loss of efficacy. However,
recreational users display a unique pattern of increasing doses, deteriorating cost-benefit ratios, and voluntary cessation. MDMA increases
body temperature and thermal stress, with cortisol levels increased by 800% in dance clubbers. It can be extremely euphoric, although
negative moods are also intensified. MDMA causes apoptosis (programmed cell death) and has been investigated for cancer therapy because
of its anti-lymphoma properties. Recreational users show deficits in retrospective memory, prospective memory, higher cognition, problem
solving, and social intelligence. Basic cognitive skills remain intact. Neuroimaging studies show reduced serotonin transporter levels across
the cerebral cortex, which are associated with neurocognitive impairments. Deficits also occur in sleep architecture, sleep apnoea, complex
vision, pain, neurohormones, and psychiatric status. Ecstasy/MDMA use during pregnancy leads to psychomotor impairments in the children.
Conclusions:The damaging effects of Ecstasy/MDMA are far more widespread than was realized a few years ago, with new
neuropsychobiological deficits still emerging.
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Full review available publicly here: http://onlinelibrary.wiley.com/doi/10.1002/hup.2318/pdf

I'd recommend reading the whole thing as it also covers some other interesting subjects such as taking MDMA in a quiet setting vs a club setting. There's also some mentions of certain deficits not being found in light users.

I had also never read anything about MDMA increasing plasma levels of cortisol, but found it rather frightening that it could elevated up to 800% in clubbers. High levels of cortisol are linked to all sorts of unpleasant things including depression, immunosuppression, increasing growth of cancer cells, etc.
 
I remember a study where they compared two groups of people: people who frequent dance clubs without using MDMA and people who frequent dance clubs and use MDMA. They couldn't find any differences between the two groups in that study, and concluded that the deficits normally found in studies of MDMA users are more likely due to the hyperthermia and other toxins (e.g. alcohol) that those individuals experience.


edit: Reference provided by chaos_destroy -

Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs

ABSTRACT
Aims In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias.

Design We compared illicit ecstasy users and non-users while (1) excluding individuals with significant life-time exposure to other illicit drugs or alcohol; (2) requiring that all participants be members of the ‘rave’ subculture; and (3) testing all participants with breath, urine and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons.

Setting Field study.

Participants Fifty-two illicit ecstasy users and 59 non-users, aged 18–45 years.

Measurements Battery of 15 neuropsychological tests tapping a range of cognitive functions.

Findings We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

Conclusions In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings—including our own—and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.
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^The paper below is possibly the one you're referring to. This paper controls the different groups well (better than most if not all other papers I have read) and focuses on non polydrug, MDMA users verse non polydrug, non-MDMA users both of which frequent the all night rave scene. They found no significant differences between groups. When users were split into heavy vs moderate the heavy users were closer to the non users than the moderate users were. The few things that showed some significance were things like impulsiveness which as they say is likely to be a contributer to them being MDMA users rather than MDMA causing that.

Either way having memory deficits etc doesn't mean you have neurotoxicity. The previously mentioned down regulation of serotonin proteins would be expected to have the same symptoms. Also taking antioxidants with MDMA in animals has been shown to abolish all so called 'neurotoxicity'. As with any drug if you go too hard you'll pay for it but unless you're being reckless I don't believe MDMA will cause any measurable long term effects.



Halpern, J. H., A. R. Sherwood, J. I. Hudson, S. Gruber, D. Kozin and H. G. Pope (2011). "Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs." Addiction. 106(4): 777-786.
 
I haven't read any of the really contemporary literature, but when I was really into it, I found nothing convincing to suggest brain damage for responsible usage. Especially 'irreversible' brain damage. My own experiences of 2 years of use confirm this (purely anecdotal of course).

Hopefully the newer studies breaking through can address the research confounds. That study by Halpern et al., (2011) looks particularly promising. Hopefully future studies can augment those findings (from my own personal bias) or at least become nearer to the 'truth'.
 
For a light hearted exploration of the relative risk of ecstasy use, you can't go past this wonderful piece by David Nutt

Naturally - he knows what he's talking about too; it's well referenced. It examines social harms as well as physical/psychological, so it's more from a public health stand point than individual health harms.
 
When I was (shamefully) abusing this substance, the comedown felt extraordinarily unnatural in terms of the 'feeling of your head', internal and external. "It feels like my brain's melting" was a joke someone made near me once. I always thought, there's no way this is good for my brain.

All those dudes are depressed now... I've been through schizophrenia and depression but the former was from cannabis.

Awesome times, but I wouldn't say it's really natural yourself to do that to yourself just for temporary highs.
 
The damage of MDMA can be greatly substantiated as the difficulty the brain has when attempting to saturate itself with serotonin after repeated use.

Considering one time use or occasianal use this effect would be greatly different than repeated or frequent use of course.

Honestly I wouldn't be concerned because the very nature of mdma keeps it safe in terms of effects rather than perceived tolerance.
 
chaos_destroy said:
The evidence that MDMA damages neurons is not strong even in animals. Over the years there has been a strong political bias in funding and hence conclusions of research and grant proposals. Most the studies use ridiculously high doses which are irrelevant to real whole situations and even still the most they ever really show is that serotonin receptors, transporters and enzymes are down-regulated which is no surprise given the strong serotonin release. If anything it would be odd if it didn't down regulate them. I know of no studies that show reliable evidence for this particularly in relevant doses.

The only study I know of that bothered to actually label SERT using GFP rather than using radio labeled binding found SERT to be internalised and degraded following MDMA exposure with no loss of actual neurons. Using the methods most papers use they would have found a reduction of neurons based on this SERT down regulation because it would have shown a lot weaker binding on the cell surface hence fewer cells have been strong enough to be counted. They are right in that if the neurons were gone they would see the same thing but they ignore the fact that the more logical and expected down regulation of SERT and serotonin receptors and enzymes would also give the same result using those tests.

The reality is that if you write a grant proposal or submit a paper that says 'drugs are bad' your way more likely to be accepted than if you say 'no significant damage found'.
Click to expand...

On the other hand, new studies in chronic MDMA users using diffusion tensor imaging have demonstrated changes in the white matter tracts, suggesting axonal loss.
 
Here is a study that used MRI spectroscopy, in which voxels decreased N-acetylaspartate(NAA) peaks signify neuronal loss. This study found significantly decreased NAA/creatine ratios in the midfrontal areas of MDMA users compared to nonusers.

Reneman L, Majoie CB, Flick H, den Heeten GJ. Reduced N-acetylaspartate
levels in the frontal cortex of 3,4-methylenedioxymethamphetamine (Ecstasy)
users: Preliminary results. AJNR Am J Neuroradiol 2002; 23(2):231–237.
 
The first one you posted found a difference in IGT scores and a change if a particular region in the brain. They found a correlation between the two also. They didn't control for poly drug use and the difference in general drug use between control and MDMA users was high. The alcohol consumption was ten fold high in the MDMA group so the study means nothing for MDMA.

Any way IGT is a test for decision making and Hanson et al. (2008 ) found IGT score to correlate with drug users in general not specific to a particular drug. In other words your ability to make decisions effects the likely hood you will take drugs. Not the other way around.

The second uses too small of a sample size and hence shows no reliable difference.


The third claims reduced N-Acetylaspartic acid in MDMA users though I'm not convinced on their analysis. They get p values of 0.03 for 2.06 +/- 0.23 vs 1.78 +/- 0.27 which seems odd given the SD massively overlaps. Also Perrine et al. (2010 ) test for N-Acetylaspartic acid levels in rats follow 'neurotoxic' doses and found no difference which suggests the difference was not actually be significant in the first place.



Hanson, K. L., Luciana, M. and Sullwold, K. (2008). "Reward-related decision-making deficits and elevated impulsivity among MDMA and other drug users." Drug Alcohol Depend. 96(1-2): 99-110.

Perrine, S. A., Ghoddoussi, F., Michaels, M. S., Hyde, E. M., Kuhn, D. M. and Galloway, M. P. (2010). "MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain." Neurotoxicology. 31(6): 654-661.
 
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