Originally appearing at http://www.nhs.uk/news/2011/02February/Pages/ecstasy-brain-damage-research.aspx. “Ecstasy does not wreck the mind,” The Guardian reported. According to the newspaper, experts have said that previous research into ecstasy was flawed and that “too many previous studies have made over-arching conclusions from insufficient data”. The news is based on a US study in 111 people that compared brain function in ecstasy users and non-users. It differed from other studies as it recruited both sets of participants from nightclubs in order to compare people with similar recreational habits. It also excluded people who took drugs other than ecstasy or drank alcohol excessively to prevent these substances clouding any effects of ecstasy. The study found that ecstasy users and non-users performed equally well in cognitive tests. However, the number of participants was low and the researchers highlight that the small sample size may have prevented an effect from being observed. Additionally, the study did not follow the participants over time to assess whether their brains had changed with ecstasy use. While the study was well conducted, illicit drug use can be difficult to research, and this research cannot confirm that ecstasy is a safe drug. Where did the story come from? The study was carried out by researchers from Harvard University and was funded by a grant from the US National Institute on Drug Abuse. The study was published in the peer-reviewed medical journal Addiction. The Guardian reported that there is no evidence that ecstasy causes brain damage. While this study was well conducted, it was relatively small and did not follow people over time. Without further research, it is not possible to say conclusively that this statement is correct. What kind of research was this? In this cross-sectional study, the researchers looked at the effects of ecstasy use on cognitive function. They pointed out that several confounding factors could have plausibly introduced bias into other research in this field, resulting in findings that have over-estimated ecstasy–induced brain impairment or toxicity. The confounding factors in these studies may have been behaviours common to people who use ecstasy that have an impact on brain function. For example, naturalistic studies that have looked at cognitive function in ecstasy users may not have compared them to non-users with similar lifestyle experiences, such as sleep and fluid deprivation that occurs from all-night dancing, which may produce long-lasting cognitive effects. The researchers point out that other studies also failed to screen participants for ecstasy, other illicit drugs and alcohol on the day of testing, leaving them open to the possibility of surreptitious drug use. Ecstasy users additionally reported extensive use of other drugs, which may potentially also lead to brain changes. In this study, the researchers performed an analysis comparing ecstasy users to non-users sourced from nightclubs. The researchers also attempted to control for possible confounding factors by excluding individuals with significant lifestyle exposure to other illicit drugs or alcohol, and by performing drug and alcohol tests on the participants. In addition, participants were asked to report their drug and alcohol consumption. They also used as a comparison group people who had similar “rave” lifestyles but did not take ecstasy. What did the research involve? The researchers advertised for participants in all-night dance venues. The participants were screened over the telephone for their use of ecstasy and other inclusion and exclusion criteria. The telephone interview also included irrelevant questions, such as questions about tobacco or caffeine consumption, to try to stop the participants guessing what the study was about. The study recruited two sets of participants aged 18 to 45 years old. One group reported either 17 or more lifetime episodes of ecstasy use, and the second group reported that they had never used ecstasy. The participants had all attended at least 10 all-night dance parties, staying awake until at least 4.30am. The researchers excluded people who: -had used cannabis more than 100 times in their life or any other illicit drug more than 10 times -had been intoxicated with alcohol more than 50 times, defined as consuming at least four drinks (12 ounces of beer, 4 ounces of wine or 1.5 ounces of distilled spirits) within a four-hour period -had a history of head injury with loss of consciousness that was judged clinically significant or a history of other medical illnesses that might affect cognitive function -were currently using psychoactive medications (however, participants reporting psychiatric symptoms but not taking medicine were not excluded) In their evaluation, the researchers asked about the participants’ history of episodes, doses and settings of lifetime ecstasy use, and took a history of psychiatric disorders from childhood to adulthood, such as ADHD, depression and anxiety. Four weeks after the initial evaluation, the participants underwent a battery of tests to assess their cognitive function (memory, language and mental dexterity) and their current mood. The participants had been asked to refrain from taking ecstasy for 10 days before these tests. The participants additionally underwent drug and alcohol testing. For statistical analyses, the ecstasy users were grouped as “moderate” users, reporting 17 to 50 lifetime episodes of ecstasy use, and “heavy users”, who had taken ecstasy over 50 times in their life. The researchers used a statistical technique, called linear regression, to model how ecstasy use influenced cognitive function. In this model, they factored in other variables that may contribute to cognitive function, such as age, gender, ethnicity, socioeconomic background, parental education level, history of ADHD and family history of psychiatric illness or substance abuse. What were the basic results? The researchers recruited 52 ecstasy users and 59 non-users. Owing to difficulties in recruiting, they relaxed their criteria for six individuals who had taken other drugs. The two recruited groups were generally similar, with the only differences being that ecstasy users were more frequently non-white, reported lower levels of parental education and had lower vocabulary than non-users. The researchers found no differences in the cognitive test scores achieved by users and non-users. When the researchers separately compared moderate and heavy ecstasy users to non-users, they found no differences in their scores for most of the tests. Relative to non-users, moderate ecstasy users scored lower in 3 out of the 40 tests, but the scores of the heavy-use group did not differ from that of non-users. How did the researchers interpret the results? The researchers suggested their study may show that “illicit ecstasy use, by itself, does not generally produce lasting residual neurotoxicity” (brain damage). They further suggest that, as they took unusual care to minimise factors that might bias results, it is plausible that the results of some earlier studies, which suggested that ecstasy impaired brain function or caused brain damage, could be attributed to these confounding factors. However, they also say that the lack of a difference in cognitive function between the groups may be because they were unable to detect an effect rather than because one did not exist. They also highlight that only six participants had very high ecstasy exposure (over 150 episodes). Given these two plausible explanations for not finding a difference, they say that the effect of ecstasy on the brain remains “incompletely resolved”. Conclusion This well-conducted research attempted to eliminate the influence of factors that could have affected earlier resea
rch into the effects of ecstasy on the brain. The study assessed ecstasy use in people who did not use any other drugs and compared them to individuals who did not take ecstasy but regularly went out dancing all night. Although the researchers took into account these confounding factors, it is not possible to say definitively that ecstasy does not affect cognitive function or cause damage to the brain because of several limitations: -This was a cross-sectional study, which means that the assessment of cognitive function was made at one point in time. It is not possible to say from these results whether ecstasy use would affect the brain over time. -The study was not randomised. This means that the two groups may have differed in respects other than their use of ecstasy. Therefore, even if a difference in cognitive function had been found, it would not be possible to say that this was definitely due to ecstasy use as differences in factors, such as education, could be responsible. -Owing to the strict inclusion criteria (people who only took ecstasy without any other drugs and non-users who attended all-night dancing venues), the number of participants was small. It is, therefore, possible that the sample was too small to detect the differences between the two groups. -Some exclusion criteria, such as having fewer than 50 sustained drinking sessions, were relatively restrictive given that the study looked at illegal drug use. Therefore, the participants may not have been representative of typical ecstasy users. It also suggested that participants may not have mixed their ecstasy use with drinking or other drugs, a behaviour that might potentially have some effect on the brain. -This study looked at cognitive function using various tests, but did not look at brain structures (such as by using brain scans). As this study was not designed to detect brain damage and did not follow people over time, any differences it might have found in brain function could not have been confirmed as permanent or temporary. This study has highlighted the importance of the confounding factors involved in this type of drug research, but has not fully resolved whether ecstasy impairs brain function.
Dr. John H. Halpern (Harvard Medical School/McLean Hospital) Responds
- NHS: “However, the number of participants was low and the researchers highlight that the small sample size may have prevented an effect from being observed.”
JHH: No study can exclude completely that there are methodological limitations. That being said, the sample size was not low or small. In fact, this is (I believe) the largest neurocognitive study of Ecstasy users ever attempted or reported. Where were these critics when all prior studies with even smaller sample sizes were relied upon almost without question just because those studies had findings of harm? There is no credibility to the claim that our study was “relatively small.”
- NHS: “Additionally, the study did not follow the participants over time to assess whether their brains had changed with ecstasy use.”
JHH: This is irrelevant if not meaningless, because we took people who had used ecstasy 20 or more times (range: 22-450 lifetime experiences). We don’t need to study individuals repeatedly to evaluate chronic, long term effects. If someone is an alcoholic for 20 years, do we need to do serial testing to confirm that damage worsens over time? That is a different study. We can compare heavy alcoholics to non-users, and such a study will indeed reflect the cumulative effect of use–no different from the study we completed.
- NHS: “While the study was well conducted, illicit drug use can be difficult to research, and this research cannot confirm that ecstasy is a safe drug.”
JHH: Who said our study was about confirming “that ecstasy is a safe drug?” In fact, we specifically stated that our report should not be twisted into asserting that MDMA is “risk-free.”
- NHS: “Without further research, it is not possible to say conclusively that this statement is correct [statement is that there is no evidence that ecstasy causes brain damage].”
JHH: As if these people ever said that about any of the prior studies that had negative findings with much smaller samples and tons of confounds. What is critical to understand here is that we don’t have these sorts of debates over the damage from alcohol. The fact is that there are 20-plus years of research in this field and it still isn’t conclusive for harm: This alone is quite telling. We don’t have this sort of debate over alcohol, so why with MDMA? I suspect that it’s quite likely that our findings have zoomed in on what has achieved the wide range of results in studies of the cognitive performance of Ecstasy users: Confounds were poorly controlled for in the past.
- NHS: “The participants had been asked to refrain from taking ecstasy for 10 days before these tests.”
JHH: In fact, we required at least 21 days from last use. This is important because almost all other research evaluated users after little to no delay from last use. Only a few other studies waited at least 14 days from last use. Why delay? So that we don’t test people in some sort of prolonged recovery phase. We were striving to evaluate for long-term effects, not capture decreased performance from most recent use. In fact, only 4 subjects were tested within 40 days from last use, with the shortest time being 25 days from last use.
- NHS: “Some exclusion criteria, such as having fewer than 50 sustained drinking sessions, were relatively restrictive given that the study looked at illegal drug use. Therefore, the participants may not have been representative of typical ecstasy users. It also suggested that participants may not have mixed their ecstasy use with drinking or other drugs, a behavior that might potentially have some effect on the brain.”
JHH: I don’t believe the NHS ever complained about polydrug use as the culprit in prior evaluations of Ecstasy users. Our study showed that any harms found in polydrug Ecstasy users may be due to other drugs or combinations of drugs. This must now be dealt with more directly than just using statistics to control for other drug use. We purposely sought out relatively exclusive users of ecstasy to zero in on the neurocognitive performance of those users, free from the confound of polydrug use. The NHS commentary points out a confound in opposition: If we just stick with polydrug users in this type of research, then the picture remains murky on harm, enabling them to stay “on message” that all drugs cause damage. Our ambition is only to engage the scientific method to elucidate useful data. We published our findings, and doubters are free to follow the published methodology and attempt to replicate our work. By the way, we did publish mostly similar results in 2004: that was our pilot data and constitutes a separate study. Our present study does not include any data from the 2004 paper, meaning that the majority of our findings are already replicated in our present report.
- NHS: “This study looked at cognitive function using various tests, but did not look at brain structures (such as by using brain scans). As this study was not designed to detect brain damage and did not follow people over time, any differences it might have found in brain function could not have been confirmed as permanent or temporary.”
JHH: This is quite bizarre from my perspective. It appears that the NHS believes that only by looking at “brain structures (such as by using brain scans)” is it possible to prove brain damage. This is false (except, of course, for visualizing images of tumors, strokes/infarctions, or other neuroanatomical damage). Images of the brain will not show that a person has damaged cognitive performance. Poor cogni
tive performance indeed can, however, indicate brain damage. Indeed, the Revised Strategic Application Test (RSAT) was developed specifically to evaluate those with traumatic brain injury and other physical injuries to the brain. As for the complaint about not following people over time, this is not a limitation of our research (see my comments above). The issue of “permanent” versus “temporary” just makes no sense: We evaluated longstanding users of Ecstasy versus non-users and we waited a long time from last use in order to focus on the longer-term functional consequences of use. Or, rather, is the NHS claiming that healthy brain function is “temporary?” It is true that no study is perfect, and that there are limitations and benefits to each approach. That being said, let’s see what other research teams might find if they follow our lead in removing the types of confounds that have plagued this area of research for far too long. I suspect that most will soldier on explaining away their study confounds rather than addressing them (which, in all fairness, is exactly what I am doing in offering up my perspective on the limitations of our present work raised by the NHS). I salute the NHS for offering a mostly fair, reasoned, and reasonable commentary on which then to debate this science.
This article adeptly summarizes the purpose, methods, and results of Dr. John H. Halpern’s latest study of the risks of Ecstasy (which showed no evidence of cognitive damage associated with heavy recreational Ecstasy use). While it rightly acknowledges that “this research cannot confirm that Ecstasy is a safe drug,” it does make some glaring errors in its conclusions about the study’s significance. This entry contains both the original NHS article and Dr. Halpern’s careful and well-reasoned response.