In response to the sensationalistic and inaccurate recent news coverage of prospective Ecstasy user studies by Dutch researcher Dr. Maartje M. de Win, MAPS President Rick Doblin, Ph.D. wrote this open letter to Dr. de Win voicing his concerns, and MAPS Clinical Research Associate Ilsa Jerome, Ph.D., wrote a special report evaluating the media’s claims and how they relate (or not) to the actual data.
[The following text has been revised upon reading de Win et al. 2005, which describes the structure of the Netherlands XTC Toxicity (NeXT) study.]
Recently there has been a lot of news coverage of a new study in ecstasy users that has been carried out in the Netherlands, with the headlines stating that Ecstasy can harm the brain of first time users, and with the stories including statements about memory loss in ecstasy users as well. (See, for example, this report from BiologyNews.net). After examining the few published reports and conference presentations, there is little to no published data supporting the worries of the researchers or the media. All the measures they used for detecting signs of damage to serotonin neurons failed to find these signs, and the significance of the one change they did find is not clear. Furthermore, the only publicly available data from these studies concerning memory in ecstasy users refutes claims of memory impairment. Hence the news coverage, and even the researchers themselves, misrepresent what the researchers actually found; little to no indication that a few doses of ecstasy harm the brain.
The studies in the news are the first published reports looking at people before and after people wrote to say they had used ecstasy at least once. In the brain imaging study, the researchers looked at participants brains after an average of 1.8 tablets (range of one to ten). The research team has also presented data at two conferences, the College on Problems of Drug Abuse (CPDD) and the Radiology Society of North America (RSNA). The published report draws upon data from the first of two planned follow-ups, with the first follow-up only including people who reported using ecstasy, both conference presentations describe data from the second follow-up, including individuals who had and had not used ecstasy, and fMRI only assessed right-handed participants. While the news articles comment on possible harm to the brain, In the published report, the researchers state that they did not find any chemical markers for neuronal injury after people used ecstasy. They found decreased regional cerebral blood volume in several brain areas, but after accounting for the number of tests they performed, the only finding that remained significant was for decreased CBV in the dorsolateral frontal cortex. People who used ecstasy reported being more impulsive, but they also reported fewer depressive symptoms. A conference presentation discussing imaging that used a marker for serotonin transporter (SERT) in people before and after taking an average of six tablets failed to find any decreased estimated serotonin transporter sites, and the other conference presentation, examining functional MRI in people before and after 2.7 tablets did not find any changes in brain activity during an associative memory task. Taken together, the published report and conference presentations did not find evidence that low dose ecstasy use damaged the brain. Instead, the researchers found a region-specific change in cerebral blood volume, increased impulsivity and decrease in depressive symptoms. Furthermore, while cumulative ecstasy use in the study was low, even the average dose in the study reporting the lowest amount use (the published report) was greater than one tablet, and the dose range across all reports and presentations was even higher. This is one of the strongest studies designed so far in that the authors used a prospective rather than a retrospective design, and it would be a mistake to ignore the study findings. However, study participants still made their own decisions concerning ecstasy use, leaving open questions about pre-existing conditions and use of other drugs. And as described above, the fact is that the researchers found that little had changed after ecstasy use.
Despite claims of memory impairment in ecstasy users, the researchers have not published any findings on memory loss, and one of the conference presentations even says they found no differences between ecstasy users and controls in associative memory performance. A number of people heard the researchers giving this presentation at CPDD. One attendee recalled hearing the presenter say, “What I’m about to tell you is probably not what you are expecting to hear.” (You can read a copy of the CPDD abstract here). However, it appears that the news reports are based upon another conference presentation, this one given at a radiology conference (see this abstract). Yet this abstract also fails to say anything specific about memory tests. Instead, the abstract describes imaging using a marker for serotonin transporter, failing to find any differences in estimated serotonin uptake sites in ecstasy users and nonusers, and instead found changes in cerebral blood flow that might be due to vasoconstriction. In the discussion of their published report, the researchers state that they have found a small but significant decrease in verbal memory in ecstasy users when compared with nonuser controls, and cite an in-press study. All we know to date about memory in ecstasy users is that the researchers have a forthcoming paper on the topic, but we don’t have the data on hand for examination, and that the comparison was made between ecstasy users and nonuser controls. We don’t know whether the change is lasting, or whether use of other substances might be involved. What’s more, this statement does not address whether ecstasy user performance changed over time, just that it changed in respect to nonusers. Without knowing more about the assessments or analyses, it is premature to say the least to draw conclusions about them. The research that comes the closest to addressing this issue is a conference presentation that failed to find any changes in cognitive function after two administrations of 1.5 mg/kg MDMA (Ludewig et al. 2003). Many previous published reports have failed to find memory problems in moderate ecstasy users who reported greater cumulative use than in this study (for instance Gouzoulis-Mayfrank et al. 2003; Halpern et al. 2004; Reneman et al. 2006). While these studies examined smaller samples, it is still surprising that so many of them failed to find any memory problems in moderate users, though they did find memory or decision making problems in heavy users. Some studies have failed to find memory differences at all (Simon et al. 2002), or found heavy users had problems with decision-making and planning, but not memory (Halpern et al. 2004). At any rate, we cannot make comparisons between unpublished data and published reports.
To conclude, both journalists and the researchers appear to be overstating or even misrepresenting findings from these prospective studies of ecstasy users. De Win and colleagues ended their paper by saying, “Therefore, and because there may be various personal and environmental factors that play a role in the occurrence of acute and long-term effects of ecstasy, it is impossible to state, based on this study, that incidental use of ecstasy is totally safe for the brain.” Yet they just as easily could have written “Therefore, though we cannot rule out the possibility that even low doses of MDMA hold some risks, we found very little evidence that incidental use of ecstasy causes any injury to the brain.” The take home message is, when confronted with news reports on the latest findings in ecstasy user research, it is worth it to track down the original research whenever possible so that you can judge the accuracy of the coverage for yourself. You can do that by visiting PubMed (www.pubmed.gov) and the MAPS Psychedelic Bibliography.
Some of these papers can be found in the MAPS bibliography.
I sent the following questions to two NeXT study authors along with a copy of the commentary above in an email sent on Dec 11, 2005.
- What was the average or usual time between each type of measurement? There were so many different types of imaging and testing that I assume they were not all performed on the same day but happened on different days.
- It looks as if there are different average cumulative doses for the MRS, fMRI and B-CIT studies. Is this a result of analyzing data from different participants or because of measurement at different points in time, or both?
- Since the average dose in the MRS study was 1.8 tablets and the range was 1 to 10 tablets, it appears that there were some outliers in the sample; did you do any analyses with the outliers excluded?
- What tests did you use when comparing memory in ecstasy users, and what did you find when examining memory and decision making before and after ecstasy use? Were the tests described in the CPDD presentation different from the tests in the forthcoming paper?
- What surprises me is that a number of studies examining cognition in ecstasy users have failed to find any differences in moderate ecstasy users, where “moderate” use is considerably greater than in this study. This includes a study co-authored by Reneman, who worked on one of the NeXT studies. I understand that previous studies examined smaller samples, but three well-designed studies, as well as other studies (such as Back-Madruga et al. 2004 and Medina et al. 2005) did not find impaired cognition in different samples. Why do you think you detected impaired cognition when others did not?
- Were there any analyses that examined the effects of use of other substances on memory or decision-making? It seems possible or even likely that people who decided to use ecstasy used other drugs as well, possibly in greater amounts than those who decided not to use ecstasy.