Health - Studies into the effects of MDMA on the human brain (The neurotoxicity debate)

[Synesthesiac]

I was browsing the archive for studies on the effects of MDMA in humans and found the study mentioned in the documentary "Ecstasy Rising" which was the most respected at the time, so I figured I might aswell write up what I find into a thread to discuss. At the time (2003) it was considered the study with the best controls and that covered the widest sample size in humans. It is still one of the most cited papers in the area of MDMA's effects on humans. It was published just after Dr Geroge Ricaurte's govenment funded study in 2002 had shown that a "common recreational dose" of MDMA caused severe damage to the dopamine systems of monkeys and maybe even could cause Parkinson's disease. This paper had to be withdrawn from the Journal Science, a very unusual step, due to issues with its accuracy. He "accidentally" actually injected the monkeys with methamphetamine, not MDMA. Whoopsie

Also, his previous 1998 study showing large permanant damage and 'holes' in the brain was later found to have a fatal flaw based on faulty data. There's a video clip about this whole fiasco I added to the archive here. Dr Ricaurte has refused to comment.

The better 2003 study by Ralph Buchert et al can be seen here: Long-Term Effects of “Ecstasy” Use on Serotonin Transporters of the Brain Investigated by PET - THE JOURNAL OF NUCLEAR MEDICINE • Vol. 44 • No. 3 • March 2003

It is still unclear whether MDMA leads to an irreversible impairment of serotonergic neurons or whether neuronal alterations are reversible after withdrawing from using ecstasy. Moreover, criticism of previous studies concerned the potential concurrent abuse of psychoactive agents other than ecstasy that might also cause a reduction of the availability of SERT.

Therefore, the aim of this study was to investigate the long-term effect of MDMA use on the serotonergic system by 11C-()-McN5652 PET in a rather large number of subjects with special regard for actual or former ecstasy abuse and abuse of psychoactive substances other than MDMA.

(SERT = Serotonin transporter)

They basically had four groups of people, Actual Ecstasy Users (who had used MDMA at least once a week right up to the test, and used an average of 827 tablets) Former Ecstasy Users (who had not used for over 20 weeks and used an average use of 793 tablets) Drug-Naive Subjects (No history of illicit drug use) and Polydrug Users (who used psychoactive substances other than ecstasy).

They found firstly that SERT density levels were lowest in certain brain regions for the group of actual ecstasy users and highest in the group of polydrug users. Which was not a big surprise. They also found that SERT density levels in the former ecstasy users was very close to the levels found in their drug-naive control subjects. Saying "There was no significant difference between these groups; there was not even a tendency". Which is very good news for fellow swimmers

They also found no difference at all in the SERT availability in 16 of the individuals who stopped using MDMA 29-20 months earlier compared with the 15 control subjects who had never used MDMA, indicating a complete recovery from their previous (quite heavy) use.

The chart below demonstrates the results quite well:


Even the people who were using MDMA right up to when the tests were performed did not show a huge depreciation in SERT density, although there is certainly a noticeable difference betweent them and the non drug users. As you can see the old users were statistically the same as the non users. They certainly did not find a 50-70% reduction like the govenment funded study found.




Whilst scanning through this I also found a couple of other studies on humans that look quite respectable that were done a year or so before the above study. This one looked at about 50 people, and used far fewer controls. Cortical Serotonin Transporter Density and Verbal Memory in Individuals Who Stopped Using 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”) - ARCH GEN PSYCHIATRY/VOL 58, OCT 2001

They found that 5-HT transporter density was lower in current users when compared to non drug users, but not in ex users. Good news there. They also found that there did appear to be a slight decrease in ex users memory recall, but they were not able to ensure their ex-users had actually not used for the last year (as they took no hair samples) and they can not completely rule out the possibility that the observed memory impairment in the MDMA-using subjects was unrelated to cannabis use or other drugs, due to various control issues.

"In summary, our data suggest that MDMA use can lead to neurotoxic changes in human cortical 5-HT brain neurons and that these changes may be reversible. However, our data also suggest that the functional consequences of MDMA on cortical brain 5-HT neurons may not be reversible because individuals who had stopped using MDMA more than 1 year earlier had impaired memory function, similar to that of recent MDMA users."



Also this slightly older study is highly cited: Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons - THE LANCET • Vol 358 • December 1, 2001

Which found nearly the same, that there are certainly short lasting neurotoxic effects from MDMA, but these seem to disappear with sufficient time. They also found that women may be more susceptable than men to this, but stilll showed a near full recovery given enough time.

Interpretation: Our results indicate that heavy use of MDMA is associated with neurotoxic effects on serotonin neurons, that women might be more susceptible than men, and that MDMA-induced neurotoxic changes in several brain regions of female ex-MDMA users are reversible.

I was wondering if anyone knows of any more up-to-date human studies to add to this thread. I always find loads of studies on animals, loads on rats, and a few on monkeys, but as Shulgin has said, testing drugs on animals is never really going to give fully accurate results, if we want accurate results we have to test the effects on the human animal. There are various problems with how results translate between species, and many studies on animals that used to be regarded as accurate when applied to humans have shown recently to be completely different when tried in human subjects. The links between species are very complex and often unreliable.

Anyone know of any more recent respected human studies with large samples? Especially any publications that have followed up on any long lasting effects on memory, that would be interesting.

So far, from these studies anyway, it looks like MDMA users have come off rather well compared to some other drugs.

Reputation Comments on this post:

	Good stuff! Thank you!
	This is excellent information concerning the topic of MDMA neurotoxicity.

[Mikey]

Nice post. Swim knows he takes a risk by using MDMA, the tradeoff for a couple of drops in IQ for the bliss of MDMA is a worthwhile one swim feels. The permanant social benefits far outwiegh the permanant health negatives in my opinion.

I think the NeXT study on MDMA's effects on serotonin and memory would be one of the best and up to date ones to answer your question. Which also has the good news of no long term side effects. Check out the MAPS research site, they have loads of good publications. Cant post links yet, but goole some text and you should find it.

The Netherlands XTC Toxicity (NeXT) Studies A team of researchers in the Netherlands embarked upon an ambitious program of research that included prospective studies of people who planned on using ecstasy in the future (De Win et al. 2005). Participants expressing interest in using ecstasy were assessed prior to use. After some reported their first use of ecstasy or soon afterwards, the team assessed these participants as well as another group that had not yet used ecstasy.

The researchers studied brain activity, estimated brain serotonin transporter (SERT) sites, neurochemical markers of brain injury, working memory, and cognitive function including verbal memory. These studies are unique in their examination of people before and after drug self-administration rather than making cross-group comparisons between ecstasy users and non-user controls. Hence findings from these prospective studies far more relevant to examining risks and benefits in human MDMA studies than the majority of previous work. In general, studies from this research program failed to find any longterm effects of low to moderate ecstasy use. They did not find any changes in serotonin uptake sites nor chemical markers of brain injury, and they found only minor regionspecific changes in cerebral blood volume (de Win et al. 2007; de Win et al. 2006; Jager et al. 2007b). While an examination of change scores before and after use indicated greater improvement in non-users than in ecstasy users, they failed to find impaired working memory after low ecstasy use (Jager et al. 2007b; Schilt et al. 2007). There are a number of problems with this research, including use of change scores and the inclusion of an individual whose ecstasy use was considerably greater than others in the cognitive function assessment. However, despite these findings, the general picture from the NeXT studies is that low to moderate ecstasy use produces very few long-term effects and is not comparable to effects found after heavy use of ecstasy and other drugs.

[Revolver123]

I'm disappointed to see that the most recent studies on MDMA are from 2003. That was six years ago folks, come on. We need some new, recent and raw data for 2009. Otherwise there is no hope to have MDMA become a legal substance (which given the lack of harm proved in the 2003 studies, it should be.)

[Beta]

Originally Posted by Revolver123

I'm disappointed to see that the most recent studies on MDMA are from 2003. That was six years ago folks, come on. We need some new, recent and raw data for 2009. Otherwise there is no hope to have MDMA become a legal substance (which given the lack of harm proved in the 2003 studies, it should be.)

I guess you answer the question: There is no new studies because the authorities don't want to legalize mdma...