Quick Review of Prepublished Paper by den Hollander et al. Citing “Preliminary Evidence of Hippocampal Damage in Chronic Users of Ecstasy”
L. (Ilsa) Jerome, Ph.D.
MAPS Research and Information Specialist
den Hollander B, Schouw M, Groot P, Huisman H, Caan M, Barkhof F, Reneman L. (2011) Preliminary evidence of hippocampal damage in chronic users of ecstasy. J Neurol Neurosurg Psychiatry. 2011 Mar 28 [Epub ahead of print].
Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display significant memory impairments, whereas their performance on other cognitive tests is generally normal. The hippocampus plays an essential role in short-term memory. There are, however, no structural human data on the effects of ecstasy on the hippocampus. The objective of this study was to investigate whether the hippocampal volume of chronic ecstasy users is reduced when compared with healthy polydrug-using controls, as an indicator of hippocampal damage. The hippocampus was manually outlined in volumetric MRI scans in 10 male ecstasy users (mean age 25.4 years) and seven healthy age- and gender-matched control subjects (mean age 21.3 years). Other than the use of ecstasy, there were no statistically significant differences between both groups in exposure to other drugs of abuse and alcohol. The ecstasy users were on average drug-free for more than 2 months and had used on average 281 tablets over the past six and a half years. The hippocampal volume in the ecstasy using group was on average 10.5% smaller than the hippocampal volume in the control group (p=0.032). These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage, in line with previous reports of acute hippocampal sclerosis and subsequent atrophy in chronic users of this drug.
The study above assessed brain volume in 17 men, 10 of them reporting an average lifetime use of 281 tablets of ecstasy (minimum 50 tablets) and seven reporting no ecstasy use. The participants were expected to abstain for two weeks prior to the study day, with abstinence verified through urinary screen on the study day. The authors state that the data is drawn from an earlier study, and it would appear to be from the sample described in Reneman et al. 2006 , since that sample used the same minimum exposure while the component of the Netherlands XTC Toxicity (NeXT) study examining heavy ecstasy users required minimum of 100 tablets [2, 3]. The ecstasy users were older than the controls (25 versus 21 years old). The researchers scanned brains with a 3 T MRI scanner, with hippocampus manually outlined by an experienced operator blind to experimental condition.
Comparisons of hippocampus were made with a univariate (one-way) analysis of variance. Ecstasy users reported using more amphetamines than controls, and an examination of drug use history suggests that, as is often the case, they used other substances more frequently as well. The researchers state of their results, “The hippocampal volume in the ecstasy-using group was on average 10.5% smaller than the hippocampal volume in the control group (3.8 ml +/- 1.6 vs. 3.4 ml +/- 4.4, p = 0.032). They reported no differences between left and right hippocampus. There were no differences in total brain volume, but the authors state, “After correcting for total brain volume, there were no differences in the proportion of total white-matter volume, but the proportion of overall grey-matter volume was on average 4.6% lower in the ecstasyusing group (51.5% +/- 1% vs. 49.1% +/- 2.4%, p = 0.022), analysed using voxel-based morphometry (VBM).” The authors remark that their earlier work found reduced serotonin transporter (SERT) sites in ecstasy users and lower performance than controls on memory tasks, but that memory task performance was unrelated to reductions in SERT sites, and offer reduced hippocampal volume as an alternative explanation for the effect.
While I am not in a position to assess imaging techniques, I can note that the study is a typical retrospective study with imperfectly matched groups with respect to drug use. The researchers addressed the effects of different drugs by performing separate analyses, examining amphetamine and cocaine use. Whether this effectively captures the effects of substance use generally, especially frequent polydrug use, is another matter. At least one prior investigation using structural imaging reported that past methamphetamine and other substance use had more general effects on brain structures between ecstasy users and non-drug user controls . For instance, while reporting no overall differences in brain volume, differences in subcortical volume were found in ecstasy users who also reported methamphetamine use compared with non-user controls. Kish found more differences in volume in specific frontal and parietal areas, often on the left side. Another knowledgeable reader of this review also expressed concerns about the data being drawn from a larger sample and the time of scanning for ecstasy users versus controls, questions left unanswered by the paper.
The finding is not a new one, as Cowan and colleagues reported on reduced grey matter in ecstasy users in 2003 . They reported finding differences in grey matter in several cortical regions and brainstem, though not hippocampus, in 31 ecstasy and polydrug users when compared with 29 non-ecstasy using controls. The two studies may have reached different findings as a result of differences in their samples, including differences in gender composition and degree of matching for drug use (the 2003 study included men and women, and the control groups were less well-matched with respect to polydrug use), sample size, or the methods used to analyze MRI (statistical mapping versus manual selection of a region of interest).
Neither group of researchers referred to what they saw as “shrinking brains.” Den Hollander offer a far less exciting quote in their report: “Taken together, these data provide preliminary evidence suggesting that ecstasy users may be prone to incurring hippocampal damage, following chronic use of this drug.” Possible causes they suggest include everything from changes in neuronal or glial (non-neuronal brain cell) structure as an indirect result of changes in serotonin, potential cerebrovascular effects, to pre-existing differences in hippocampal structure, to the effects of other drugs taken along with ecstasy. As of now, all of these explanations are hypothetical, though it is notable that substance use is generally higher in the ecstasy user sample. These findings have few implications for use of MDMA in clinical research studies, given the minimum reported lifetime exposure of 50 tablets, and given that ecstasy is a product that varies in content and purity.
Additional commentary: Upon examining this report, human neuroscience researcher Matthew Johnson noted that the researchers did not do a convincing job at “matching” the ecstasy users and control participants on other drug use. The ecstasy users had considerably more use of other drugs, but the statistical tests of whether the groups differed in this respect lacked sufficient power to detect differences in drug use.
- Reneman, L., et al., Neuroimaging findings with MDMA/ecstasy: technical aspects, conceptual issues and future prospects. J Psychopharmacol, 2006. 20(2): p. 164-7
- Jager, G., et al., Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study. Neurop
acology, 2008. 33(2): p. 247-58.
- de Win, M.M., et al., Neurotoxic effects of ecstasy on the thalamus. Br J Psychiatry, 2008. 193(4): p. 289-96
- Kish, S.J., et al., Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study. Brain 2010,133(6):1779-1797.
-  Cowan, R.L., et al., Reduced cortical gray matter density in human MDMA (Ecstasy) users: a voxel-based morphometry study. Drug Alcohol Depend, 2003. 72(3): p. 225-3.
The results of a recent brain imaging study claiming an association between long-term recreational Ecstasy use and damage to the hippocampus (a deep brain region responsible for learning, memory, and other cognitive functions) has the media in a frenzy. Media outlets all over the world (such as Bloomberg Businessweek) leaped at the chance to interpret the study’s results as evidence that Ecstasy causes the brain to actually shrink. Some (like The Guardian) have even gone so far as to suggest that Ecstasy use is correlated with Alzheimer’s disease. One overenthusiastic writer at TopNews.us even claims that Ecstasy actually causes Alzheimer’s disease, despite the complete lack of supporting scientific evidence. By contrast, the results of a recent meticulously-designed government-funded study by Harvard University’s John Halpern, M.D., reporting no association between recreational Ecstasy use and cognitive damage, have been largely ignored by these media sources, which begs the question: Are journalists really doing their homework?
Thankfully, a little bit of careful attention to the actual science provides a powerful antidote to this kind of reckless reporting. MAPS Research and Information Specialist Ilsa Jerome, Ph.D., has written a quick and well-reasoned summary of the study’s results, and points out that despite the media frenzy, the study suffers from the usual shortcomings of most observational studies of recreational Ecstasy use, and should be taken with several milligrams of salt.