MDMA’s neurotoxicity is the topic of this and many future editions of Dose of Science. The question is not whether MDMA is neurotoxic in an absolute sense, but rather, what is the extent of the damage at various dosing regimens. Stephen Kish’s study  from 2010 aims to clarify the picture by employing a range of neuroimaging techniques and cognitive tests on a large sample while controlling for many potential confounding factors.
The control (n=50) and the ecstasy group (n=49) was matched with respect to age, gender composition and race. There were, however, statistically significant differences between the groups: ecstasy users spent less years in education, had a lower estimated premorbid IQ and had a marked increase in alcohol consumption (3.1±0.4, as against the control group's 1.4±0.3 drinks/week). Another difference, of course, was the history of ecstasy use. Members of the ecstasy group had a mean of 45 days' abstinence from the drug. Users had a monthly mean dose of 5.3 ±1.3 pills (2.2 ± 0.3 pills/use and 2.2 ± 0.3 use/month), although the distribution was skewed as the median is only 2.3 pills/month.
MDMA is the active ingredient of “classic” ecstasy pills. Ecstasy, however, may or may not contain MDMA, along with other psychoactive ingredients. With the rise of new psychoactive substances since the early 2000s, pills have become more adulterated. As a consequence, not even users know what drug is in their pill, and this uncertainty makes it more difficult to interpret studies of ecstasy users. To overcome this problem, Kish’s team have used hair testing to analytically confirm that subjects in the ecstasy group consumed MDMA (hair analysis also provided information about a range of other drugs).
MDMA has been shown to induce serotonergic neurotoxicity in a range of rodent and primate species (serotonergic neurotoxicity means damage to the neurons that produce serotonin). Serotonin is one of the major neurotransmitters in the brain. It is a chemical that is released in between neurons to transmit the electrical signal between them. There are many other neurotransmitters, dopamine for example, but MDMA seems to specifically damage serotonergic neurons. In animal studies, various post-mortem (after death) methods can be used to assess MDMA-induced neurotoxicity , but these techniques are not viable for human studies.
In humans, the binding potential of serotonin transporters (SERT) can be measured as a proxy for the condition of the serotonin system. The advantage is that SERT binding potential can be measured using the non-invasive technique of positron emission tomography (PET) imaging. SERT is a protein which is responsible for bringing back serotonin from the intercellular space within the cell body where it is recycled. If there is often an excess amount of serotonin available, the brain adjusts its own biochemistry by decreasing the number of serotonin transporters, resulting in lower SERT binding potential. Hence decreased SERT binding potential indicates a damaged serotonin system.
PET scans revealed a significant decrease, among ecstasy users, in SERT binding potential in the cerebral cortex and the hippocampus; no differences, however, were found in the midbrain, thalamus and other sub-cortical areas. These results suggests that the ecstasy-induced damage is highly specific to articular areas of the brain. A stepwise linear regression model was used to assess which demographic and drug history-related variables could predict the changes in SERT binding potential. The decrease in SERT was related to the total time of ecstasy use and maximum dosage, but it was not related to gender, psychiatric status, structural brain changes, hormonal levels or genetic background. 32 subjects in the ecstasy group co-used methamphetamine, which has also been shown to decrease SERT levels. The pattern of lower SERT levels was similar in the two subgroups (ecstasy users who also used methamphetamine versus ecstasy users who did not use methamphetamine), indicating that the totality of the SERT decrease could not be explained by methamphetamine use in the sample.
To further evaluate possible MDMA-induced changes in the brain, magnetic resonance imaging (MRI) was used to assess brain volume changes. There was no significant association between reduced brain size and ecstasy use. There was, however, a significant reduction in grey matter (grey matter is composed of the cell bodies of neurons), among users who also consumed methamphetamine. The use of other drugs (cannabis, cocaine) was not associated with volumetric changes.
Ecstasy users typically had lower SERT binding potential, but most of them fell within the range of the control group. The question therefore presents itself, whether there are any functional differences between the groups? To assess this possibility, a range of cognitive tests were conducted in the domains of memory and executive function. In general, ecstasy users performed worse, but “the magnitude of the mean test score differences was modest and the variance and distribution of scores showed a near total between-group overlap”. The normal or close to normal cognitive performance is consistent with other studies. The differences in cognitive tests persisted even after allowing for IQ and and years spent in education, although the authors suggest that “[users] may have drifted to a poor performance peer group because of inherent premorbid cognitive issues” (subjects in the ecstasy group also had a lower estimated premorbid IQ).
Another concern is that the decreased SERT binding might cause psychiatric disorders, as serotonin has often been linked to mood and perception. 12 subjects in the ecstasy group had some depressive and anxiety-related symptomatology. SERT binding among these 12 users, however, was not significantly different from ecstasy users without a psychiatric problem; hence the study found no evidence to link low SERT binding potential to mood disorders.
So what was learned from the paper and what further research does it suggest? The study shows that ecstasy users have lower SERT binding potential, which indicates damage to the serotonin system. The extent of the damage was related to the total time of use and maximum dose. The ecstasy group also showed somewhat poorer performance on cognitive tests, but lower SERT could not be linked to mood disorders.
MDMA decreases SERT binding potential, but it is likely that the study overestimates the effect. 65% of the ecstasy group co-used methamphetamine, which itself decreases SERT. SERT binding averaged across all brain regions is -9.5% among subjects who only used ecstasy (n=17), but it is -18% for those who co-used methamphetamine (n=32). Similarly, some cognitive impairment within the ecstasy group could be explained by co-use of methamphetamine (which is known to cause cognitive deficits ). To improve our understanding of MDMA-induced serotonin damage and cognitive impairment, future studies should exclude subjects from the ecstasy group who also used methamphetamine.
Finally we note that the study aims to characterise “low and moderate ecstasy users”, but it is questionable whether a mean of 5.3 ±1.3 pills/month is really characteristic of low profile users. In comparison the “grandmother of MDMA”, Ann Shulgin, has suggested that the substance should not be used more than four times a year . In this lower dosage regimen damage is likely to be proportionately smaller.
: Kish, Stephen J., et al. "Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C] DASB and structural brain imaging study." Brain 133.6 (2010): 1779-1797.
: Simon, Sara L., et al. "Cognitive impairment in individuals currently using methamphetamine." The American Journal on Addictions 9.3 (2000): 222-231.
:https://www.erowid.org/culture/characters/shulgin_alexander/shulgin_alexander_interview2.shtml (accessed on Oct 25 2015)