Five years after their first imaging study of ecstasy users (McCann et al. 1998), McCann and colleagues have published another imaging study comparing ecstasy users and non-ecstasy user controls (McCann et al. 2005). The new study employs better imaging methods than the first study, but it still failed to match ecstasy users and controls on substance use. In this study, the researchers performed two brain scans using two different radioactively labeled drugs, or "ligands," one of which they had used in the previous study. They found that both ligands produced similar scans, and that ecstasy users had lower estimated levels of serotonin transporter sites in a number of brain areas, such as the occipital cortex, dorsolateral pre-frontal cortex, and parietal cortex. People who had refrained from ecstasy use for a longer period of time had less reduction in estimated serotonin transporters, and people who used ecstasy more frequently or at higher doses had greater reductions. The difference between estimated serotonin transporter binding in ecstasy users and controls was generally greater than seen in the most recent study using one of the same ligands. Study results suggest that repeated ecstasy use is associated with reduced estimated serotonin transporter binding, but the findings do not suggest that people receiving MDMA in clinical trials face similar risks. Even the authors state that their study findings may not be applicable for people who have used ecstasy on fewer than 25 occasions.
McCann and colleagues measured estimated levels of serotonin transporter by performing positron emission tomography (PET) scans using ligands that latch onto (or bind with) the serotonin transporter. One ligand is referred to as McN5652, and the other is DASB. The first drug has already been employed in previous reports, including the first study these researchers performed, and more recent reports by Buchert and colleagues (Buchert et al. 2003; Buchert et al. 2004), and the other drug is a newer compound with a better ratio of specific to non-specific binding (meaning it is more likely to bind to serotonin transporter than to other proteins or receptors).
The researchers performed two brain scans, one with McN5652 and one with DASB on 23 ecstasy users and 19 non-ecstasy user controls, with both scans performed on the same day. Ecstasy users were 10 women and 13 men, average age of 22, and non-ecstasy users were 11 women and 8 men, average age of 26. The study enrolled only ecstasy users who reported using ecstasy on 25 or more occasions. Ecstasy users' average lifetime ecstasy use was approximately 97 occasions, with lifetime use ranging from 28 to 324 occasions), an average dose per use of 1.8 tablets per occasion, and an average duration of nearly three years (34.8 months). Self-reported time since last use was 4.7 months (between 141 and 146 days). Ecstasy users reported having used a greater number of substances than controls. For example, 22 ecstasy users had used cannabis at least once, 11 had used stimulants, and 13 had used ketamine, while only 7 controls had used cannabis, one had used stimulants, and none had used ketamine. All participants had to report no drug use for two weeks prior to the study day.
McCann and colleagues first performed the PET scan with McN5652, followed by a scan using DASB, with average time between scans of 135 minutes, and with scans normalized through measuring ligand metabolites in blood taken 5, 15, 30, 60 and 90 minutes after each scan. The researchers used two different means of examining scans, including assessment in 15 regions of interest by a person blind to participant condition, and a model that compared areas with the cerebellum, a brain area with few serotonin transporter sites. McCann et al. also correlated regional McN5652 or DASB binding with time since last use and "intensity" of ecstasy use (undefined, but appears to be frequency of use, possibly along with average dose per use.) McCann et al. found that McN5652 and DASB produced similar scans, though scans with McN5652 detected a few more significant differences in regional binding between ecstasy users and controls. The researchers found that ecstasy users had lower global, or overall, levels of specific binding, implying that ecstasy users had lover serotonin transporter levels than non-user controls. Both McN5652 and DASB scans detected lower binding in ecstasy users in regions such as the occipital, parietal and temporal cortex, dorsolateral prefrontal cortex, and hippocampus. While ecstasy users had lower estimated serotonin transporter levels in subcortical regions, such as thalamus, caudate and putamen, the degree of difference was comparably small. Percentage of difference ranged from 9% (for ventral pons, after McN5652) to 68% (in occipital cortex, with DASB), most percentages ranged from 20% to 40%. Finally, correlational analyses found a positive association between global McN5652 binding and length of abstinence from ecstasy, implying less reduction in estimated serotonin transporter binding with continued abstinence from ecstasy, and an inverse (negative) association between global McN5652 binding and "typical monthly use". Correlational analyses using DASB scan data produced similar results. McCann and colleagues interpret these findings to mean that continued ecstasy use is associated with changes in serotonin transporter binding, and that greater use of ecstasy in a month is associated with reductions in serotonin transporter sites.
This is the first imaging study in ecstasy users to employ a new ligand, DASB, and the first to examine estimated serotonin transporter binding in cortical as well as sub-cortical areas. This study is also the first to "normalize" scan data through assessing blood levels of ligand metabolite over time. This study found considerably larger reductions in estimated serotonin transporter sites than those reported by Buchert and colleagues (Buchert et al. 2003; Buchert et al. 2004). However, unlike the previous study, this study did not compare current ecstasy users with former users. Buchert and colleagues found lower estimated serotonin transporter sites in current ecstasy users, but failed to find reductions in former users, who reported no ecstasy use for at least six months. The findings from the Buchert team suggest that ecstasy-related reductions in brain serotonin transporter sites are transient. A more significant methodological flaw is that the present study failed to match ecstasy users with non-users on degree and type of substance use. This means that ecstasy users were more likely to take a number of other substances than non-users. Buchert and colleagues solved the problem of matching for drug use by having three control groups; former ecstasy users, polydrug users, and non-drug users. Other researchers who studied planning and memory in ecstasy users and controls dealt with this difficulty by recruiting both groups from a sample reporting minimal drug use (Halpern et al. 2004). The failure to match groups on drug use means that while the imaging techniques used in this study are superior to those used by Buchert and colleagues, the study design suffers from a grater number of methodological flaws. Because of these problems, it is possible that some of the differences in estimated brain serotonin transporter sites are related to use of other substances, such as stimulants, or in some pre-existing condition that leads people to use ecstasy and other drugs. As is true of most studies in ecstasy users, interpretation of study results is limited by small sample size and retrospective study design (meaning the researchers imaged brains after people had chosen to use ecstasy rather than imaging brains before and after ecstasy use). It is also possible that adulterated or fake pills sold as MDMA but containing other substances, such as methamphetamine or MDA, might also incur some of the effects attributed to "ecstasy."
PET scans do not measure serotonin transporter levels directly, instead measuring radiation given off by drugs that can bind with serotonin transporter. Furthermore, there may be several reasons for differences in serotonin transporter site levels, so having lower transporter levels does not necessarily imply damage to serotonin axons, even if studies in non-human animals have found more direct signs of damage after MDMA administration (e.g. Callahan et al. 2001). Nevertheless, this most recent study may represent a better view of the brain serotonin system in ecstasy users than previous imaging studies, finding that ecstasy use is associated with reductions in presumed numbers of serotonin transporter sites.
McCann and colleagues acknowledge that they did not find any behavioral differences in the ecstasy users they studied despite detecting lower levels of estimated transporter binding, and they also state that their results may not be applicable to people with lower lifetime ecstasy use. They noted that the relationship between changes in the brain serotonin system and other changes, such as subtle impairments in verbal memory, are not clear. In fact, when imaging and cognitive testing has been performed in the same samples, changes in one area do not seem to be related to changes in the other (compare Buchert et al. 2004 with Thomasius et al. 2003). This study does not change our estimation of risk involved in clinical trials of MDMA, and aside from a potentially better picture of brain serotonin transporter sites, the information offered in this paper is not in itself novel.