Brief comments re Reneman, L, Booij, K, de Bruin, K, Reitsma, JB, de Wolff, FA, Gunning, WB, den Heeten, GJ, van den Brink, W, (2001) Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons.
Lancet, 358: 1864-1869

Comments by Rick Doblin, Ilsa Jerome, George Ricaurte, Una McCann and Alex Gamma

Preliminary Comments/Overview

Here are some comments by Rick Doblin and Ilsa Jerome about the paper by Reneman just published in Lancet on Ecstasy and Women, and reported on by the AP in papers all over. MAPS is developing a rapid response capability to comment on media reports about significant MDMA-related research.

This Lancet paper was reported in the Boston paper today, with the headline, "Party drug could harm women more than men, study says." The research data tells a different story, in that men are not actually harmed less than women, they are not harmed at all even from heavy use, average 530 tablets! In this context, harm is defined only in terms of SERT reductions, in the absence of any demonstrated negative functional consequences in this population of subjects.

First, a missing transporter does not mean a dead cell, it just means nerve terminal degeneration. This study shows that the serotonin levels in women return to baseline after a period of abstinence of a year. This demonstrates regeneration and would not occur if the cells themselves were dead. Second, this research is consistent with research conducted by Dr. Vollenweider's MDMA research team at the U. of Zurich, which found that women are somewhat more sensitive than men to the effects of MDMA, when given equal amounts in mg/kg. Third, this research lends further support to the safety of the clinical use of MDMA.

Summary and Comments

Recently Reneman et al have published a report comparing binding of the radioligand beta-CIT, a potential measure of brain serotonin transporter binding sites, in 15 current moderate ecstasy users, 23 current heavy ecstasy users, 16 former ecstasy users and 13 non-user controls. Comparisons of these scans suggest that women who have used at least 50 ecstasy tablets (Mean for both genders = 530 +/- 621.1) may experience a decline in serotonin transporter binding sites, a possible measure of neurotoxicity to the serotonin system, while men who report using similar amounts of ecstasy do not have lower serotonin transporter binding sites. (Mean, women Ð mean, mean, mean = -630.8). No reduction in brain serotonin transporter sites was seen in men and women who reported a lifetime use of 50 tablets or less (Mean for both genders = 28.6 +/- 17.8, women Ð men = -2.1). Differences in serotonin binding sites no longer existed in men and women who had reported using at least 50 ecstasy tablets, but had abstained from use for at least a year (Mean for both genders = 268.1 +/- 614.3, women Ð men = 282.4). These findings suggest that women may be more vulnerable to long-term reduction in serotonin transporter sites after heavy ecstasy use, but that the long-term effects may be reversible after prolonged abstinence. If confirmed, the findings reported by Reneman and colleagues indicate that men and women given MDMA in research studies and therapeutic trials will not have reduced serotonin transporter sites afterwards, since the number of doses used in research studies falls far below that used by the moderate ecstasy users examined in this study. Therapeutic use in men or women involves much fewer than 50 tablets, with MDMA taken while resting in cooler environments with adequate fluid replacement. No reductions or any negative functional consequences, which is what really matters, are to be expected in either male or female patients enrolled in clinical trials.

The findings reported by Reneman and colleagues also suggest that changes in serotonin function are not permanent, and that there may be a threshold dose below which gender-linked decreases in serotonin function are absent or greatly reduced. The findings reported in this study are very interesting, especially with respect to potential gender differences in long-term drug effects. Future research may want to examine the nature and causes of gender differences in vulnerability to ecstasy-related changes in the serotonin system.

Reneman et al examined six different brain regions in men and women from all four groups (non-user, moderate user, heavy user and former user). All individuals in all groups recruited from the Amsterdam rave/dance event scene. Efforts were made to control for estimated verbal intelligence, age and occurrence of depression. They measured number of serotonin binding sites in selected areas of the brain by using radiolabeled beta-CIT, a drug (ligand) that binds to both serotonin and dopamine transporter sites. Specifically, beta-CIT binding in a specific brain area was compared with beta-CIT binding in cerebellum as a way of measuring amount of serotonin transporter sites. Reneman et al compared samples across group and across gender. Brain areas examined were frontal, temporal, parieto-occipital and occipital cortex, thalamus and midbrain.

Examining scans of men and women in all four drug-use history groups, Reneman and colleagues found that drug use history did not reduce serotonin transporter binding sites (measured by beta-CIT binding ratios) in male ecstasy users, whereas heavy ecstasy use was associated with lower serotonin transporter sites, as measured by beta-CIT binding, in women. Men and women reporting no ecstasy use had similar rates of beta-CIT binding, and women who had abstained from ecstasy use for at least a year no longer differed from non-users or moderate users in amount of putative serotonin transporter sites measured by beta-CIT binding ratios. When individual brain areas are examined separately, it appears that women who had abstained from ecstasy use and perhaps women reporting use of less than 50 ecstasy tablets might have had lower beta-CIT binding in occipital and parieto-occipital cortex when compared with women reporting no ecstasy use. However, these differences are trends only and do not reach statistical significance.

Findings of increased vulnerability to the long-term effects of repeated ecstasy use should draw more researchers to examine potential gender differences response to various drugs, including psychoactive drugs. It has been common in the past to rely on findings from studies conducted with men to both men and women. While it is not appropriate to assume that men and women will always differ in response to drugs or any other factor influencing physiological function, findings like those reported by Reneman and colleagues remind us that it is also inappropriate to assume that men and women respond identically to a substance or condition. Future research into gender differences in the effects of repeated use of ecstasy and other substances is warranted.

Male participants in this study reported using a higher number of ecstasy tablets than did women. However, when considering each dose, women may have been using higher doses than men in relation to body weight. Information on male versus female body weight is not provided in the paper, so it is difficult to ascertain whether this was the case or not in this group of men and women.

This paper does not address cognitive function, either across gender between ecstasy users and non-users. Previous publications by the same author have found differences in verbal memory associated with repeated ecstasy use, but no gender-specific differences in the effects of ecstasy use on verbal memory. This is particularly notable as one of the studies of verbal memory was conducted on a sub-set of the sample described in this study (the non-user controls, current heavy ecstasy users and former ecstasy users Ð see Reneman et al, 2001). To my knowledge, no other study has reported gender differences in cognitive deficits after ecstasy use. Hence there appears to be a discrepancy between gender differences in serotonin transporter site density and verbal memory performance. This discrepancy may merit further research. However, it should also be recalled that only two studies have found serotonin function more affected by repeated ecstasy use in women; it is possible that this finding will not withstand future attempts at replication.

While this study may provide us with information concerning the effects of repeated ecstasy use, a number of factors make it difficult to generalize to the use of MDMA in research or therapy. As is the case with most retrospective studies comparing ecstasy users with non-users, the ecstasy users use many other drugs besides ecstasy, and they use a greater quantity of drugs than do non-users. For example, heavy ecstasy users, reported at least some use of amphetamines and cocaine, while non-users reported no use of either drug, and heavy ecstasy users reported using an average 81.64 joints in 3 months, compared to 3.47 joints in non-users and 53.58 joints in moderate users. As well, street doses of ecstasy vary in potency, purity and content, so that reported ecstasy use is not equivalent to MDMA use. The same methodological difficulties connected with other retrospective comparisons of ecstasy users with controls that have been addressed elsewhere (see Baggott and Jerome, 2001 (www.maps.org/research/mdma/protocol/litreview/) and Gamma, 2000, (www.maps.org/research/mdma/mdmamemory) are applicable here as well. Continuing research into the potential long term effects of repeated ecstasy use may want to examine individuals drawn from outside of the dance event/rave culture in addition to individuals within this sub-culture. Such comparisons may be able to separate the effects of ecstasy use from the effects of other variables associated with frequent dance event attendance, such as lack of sleep, nutritional variables or prolonged exercise in a hot room.

Using discrete measures of depression (such as clinical diagnosis) may not be able to fully eliminate differences due to depression. A better choice may be using a continuously scored measure (such as the Beck Depression Inventory (BDI) or similar measures). Using continuous measures of depression would allow for the detection of subsyndromal depression in all groups, and as Gamma suggests, this might better control for the confounding effects of depression across and within groups.

The findings reported by Reneman and colleagues suggest that women may be more vulnerable to reduced serotonergic function or serotonin site reduction after repeated ecstasy use. However, the findings also suggest that ecstasy-related reductions in serotonin transporter site density may be temporarily, and that women reporting a lifetime exposure of less than 50 ecstasy tablets are far less vulnerable to reductions in serotonin transporter site density. The findings described in the Lancet also suggest that men and women receiving MDMA in research studies or in therapy are unlikely to have reduced serotonin transporter binding sites afterwards. Not only are these settings significantly different in environmental features, such as ambient temperature, but the doses used in research and therapeutic settings are far below those reported by moderate ecstasy users in Reneman's study.

Comments by George Ricaurte and Una McCann

"Assessing long-term effects of MDMA (Ecstasy)" (read full text)

"Although the study is timely and potentially important, the small sample size and methodological questions limit confidence in the conclusions about differences between sexes or possibility of reversibility of the effects of MDMA in human beings," Dr. George A. Ricaurte and Dr. Una D. McCann from Johns Hopkins University School of Medicine, Baltimore, Maryland, comment in a journal editorial.

"Studies in larger cohorts of both sexes, free of psychiatric illnesses in which serotonin is implicated, are needed," they add.

Comments and Counterpoint by Alex Gamma

"Let me comment on the Reneman et al paper and Rick's comments on it:

'Women show no reductions from up to 50 tablets. Women who take above that amount show some reductions but they are reversed within a year or so of abstinence.'

Rick, it is not completely true that the reduction in serotonin transporter (SERT) in female heavy (>50 tablet) E users reverses completely after one year of abstinence: Ex-Ecstasy users (as well as moderate Ecstasy users) compared to controls were found to have lower SERT levels in the parieto-occipital and occipital cortex. (This was 'only' a statistical trend, but there has never been a justification for drawing a strict line at the 5% probability level, discarding everything as unimportant that falls above this line.) One interpretation is that the parietal/occipital cortices may be particularly sensitive to the effects of Ecstasy, and may be those areas that do not completely recover. This is in agreement with the Semple study showing SERT reductions in posterior brain areas, and also with our own EEG results showing alpha frequency changes in occipital and temporo-occipital cortex in heavy Ecstasy users.

Some technical comments on the study:

The study seems well-designed and offers interesting and valuable results. One problem is that the SPECT ligand used is selective for both the SERT and the dopamine transporter (DAT), although, as Reneman argues, it is plausible that the results reflect SERT rather than DAT changes.

Another problem is the question of depression. Reduced SERT levels can be found in depressive patients, hence the question whether the study results may be due to depression. To address this possibility, Reneman and colleagues included the presence of a diagnosis of depression as a confounding variable into their analysis. Furthermore, the results of the study did not change when the subjects with depression were excluded from the analysis.

The problem, however, lies in the fact that the depressive spectrum is by no means exhausted by the cases with a DSM diagnosis. The DSM diagnosed cases constitute only the tip of the iceberg, and below the surface there are many more sub-diagnostic and symptomatic cases that are clinically and biologically relevant. In this case, if there were more subdiagnostic depressive cases among the E users than the controls, the problem of depression as a confounder would come back in through the backdoor. Optimally, therefore, there should be control not only over DSM diagnosed depression (or psychiatric illness in general), but also of subdiagnostic cases.

Some meta-technical comments:

This is one more paper in which Ecstasy is equated with MDMA. This is really something that educated researchers should no longer do.

In the abstract, the researchers state that neurotoxicity of MDMA in humans has been 'shown'. I think a little more caution would be in place here. While in animals MDMA neurotoxicity is well established, the same is not true in humans. True - it is a likely and plausible possibility, but for the sake of being as objective and close to the data as possible, we should avoid such potential overinterpretations.

Introduction: something that strikes me here and has done so in previous research papers: there is mention of the 'perceived safety of MDMA'. But who actually perceives it that way? If anything, it would rather seem that media and research generally spread a picture of MDMA/Ecstasy as harmful. Maybe ten years ago, users perceived Ecstasy as safe, but today?

The discussion is quite balanced. The important limitations and alternative explanations are addressed, although one could argue that the complete lack of effects in men even after 530 consumed doses would have deserved more emphasis, given that it would not have been expected in the current rather alarmist research climate."

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