This study confirmed the results of recently published [11
C]DASB studies (Erritzoe et al, 2011
; Kish et al, 2010
; McCann et al, 2005
), reporting that MDMA use is associated with significantly lower cortical SERT availability following a short period of abstinence. This study also revealed that postsynaptic 5-HT2A
receptors were upregulated in the regions where SERT was lower, an observation that might capture a compensatory upregulation of these receptors secondary to a state of 5-HT depletion.
The strengths of this study include the use of the most selective radiotracers currently available for SERT ([11C]DASB) and 5-HT2A receptors ([11C]MDL 100907), and a fully quantitative approach to BPND derivation that included measurement of arterial input function. While BPND can be derived without an arterial input function, the use of this outcome measure to assess between group differences implies the assumption that the nonspecific binding does not differ between the groups. In this study, this assumption was verified (no between group differences were observed in cerebellar VT; ), which validates the use of BPND as an outcome measure for between group comparison.
The weaknesses of this study include the relatively low number of subjects and the fact that MDMA users also used other drugs, mainly alcohol and cannabis. Previous work established that alcohol abuse or dependence per se
is not associated with alterations of 5-HT parameters measured in vivo
(Erritzoe et al, 2009
; Martinez et al, 2009
). To our knowledge, no studies have yet demonstrated the integrity of these 5-HT parameters in cannabis users. Subjects included in this study also occasionally used other drugs. To find subjects with a decade of exposure to MDMA and no exposure to alcohol, cannabis, or other drugs is extremely difficult. To control for the use of other drugs, some studies of SERT availability have included a control group of polysubstance users with no exposure to MDMA, and failed to report alterations of SERT in this group (Buchert et al, 2003
; Selvaraj et al, 2009
). Some studies have demonstrated lower SERT binding in users of methamphetamine (Kish et al, 2009
; Sekine et al, 2006
). Thus, the possibility that other drugs might have contributed to the alterations of the 5-HT parameters observed in the MDMA users cannot be strictly ruled out, but is unlikely given the small number of subjects with a history of methamphetamine use in this sample (n
In this study, current MDMA abusers showed lower cortical SERT binding compared with controls. The monitored period of abstinence before the scans was relatively short (2 weeks), raising concerns that residual binding of MDMA to the SERT might have contributed to the reduced SERT availability. However, the regional specificity of this effect makes this explanation unlikely: While the finding was global in the cortical regions, it was more pronounced in the medial prefrontral, temporal, and occipital cortex and when comparing cortical to subcortical regions.
It is theoretically conceivable that a decreased 5-HT function in the cortex might be a predisposing factor to the use of MDMA and that the use is a consequence rather than a cause of 5-HT dysfunction. While this study cannot refute this hypothesis, the experimental evidence in animals of the selective neurotoxicity of MDMA toward 5-HT neurons supports the proposition that sustained MDMA exposure is directly responsible for the alterations of 5-HT parameters observed in this study.
Given the clinical and geographic heterogeneity of the MDMA user populations studies, it is remarkable that 5 out of 5 studies, including this one, performed with [11
C]DASB in current (ie recently abstinent) MDMA users showed lower SERT availability in neocortical regions (). The four other studies have also reported alterations in the hippocampus. Conversely, all studies but one showed unaltered levels in the striatal regions or in the thalamus, and all studies reported unaltered levels in the midbrain. The low expression of SERT in the cortex () and the resulting small and noisy specific signal recorded with [11
C]DASB in this region (Frankle et al, 2006
) makes this body of results particularly impressive. If anything, alterations of SERT in the cortex should be more difficult to detect than in the SERT-rich regions of the thalamus, midbrain, and striatum. Studies with higher affinity SERT radiotracer such as [11
C]AFM might be useful to further assess these findings (Huang et al, 2002
[11C]DASB Studies in Current (n=5) and Former (n=1) MDMA Abusers
These PET findings are entirely consistent with the preclinical literature that showed that vulnerability of 5-HT neurons to MDMA is related to the axonal length (Molliver et al, 1990
), making 5-HT neurons with the longest axons, innervating the cortex more susceptible to MDMA damage compared with the neurons innervating subcortical structures. Even within cortical regions, a difference is observed between the medial and dorsal regions, with dorsal regions associated with longest axonal lengths being more affected than the medial regions ().
The only [11
C]DASB study that failed to detect changes in MDMA users is the study of Selvaraj et al (2009)
, who investigated [11
C]DASB in 12 former MDMA abusers (last use >1 year before the scan). This finding suggests that the lower SERT availability observed in current users might be reversible. However, caution should be used before adopting this conclusion. As mentioned earlier, [11
C]DASB measurement in the cortex is noisy, and the Selvaraj et al (2009)
study did not include a positive group of current users. Thus, more work, including longitudinal studies of abstinence, is needed to test the reversibility of these changes. We were not able to demonstrate any correlation between length of abstinence and SERT or 5-HT2A
binding, but a relatively small sample size and a small range of duration of abstinence compared with other studies that found indicators of reversibility may have been limiting.
PET [11C]DASB studies per se cannot ascertain if the lower SERT availability observed in the cortical regions of current MDMA users corresponds to a loss of these terminals due to the neurotoxic effect of the drug or a functional downregulation of SERT expression as a homeostatic reaction to the repeated MDMA exposures, or some combination of both factors.
To our knowledge, this is the first study to evaluate 5-HT2A
receptors in recent MDMA users with PET and a truly selective 5-HT2A
receptor PET ligand, [11
C]MDL 100907. MDMA users showed higher 5-HT2A
receptor availability compared with control subjects in the cortex. Initial findings from SPECT studies performed with [123
I]R93274 suggested a complex effect of MDMA on 5-HT2A
receptors dependent on duration of abstinence, with 5-HT2A
receptor availability lower and higher in current and former MDMA users, respectively (Reneman et al, 2002
). Because of the low signal-to-noise ratio of [123
I]R93274 (Abi-Dargham et al, 1997
), confirmation with better ligands currently available was necessary. Recently, Erritzoe et al (2011)
reported no difference in 5-HT2A
receptors measured with [18
F]altanserin in the cortical regions of current MDMA users. Compared with [11
C]MDL 100907, [18
F]altanserin is less selective for 5-HT2A
receptors, as it displays nonnegligible affinity for 5-HT2C
receptors (Kristiansen et al, 2005
). Yet, this factor is unlikely to account for these different results (Kristiansen et al, 2005
). More likely, the more prevalent use of hallucinogens in the Danish study might explain the difference in the findings, as these drugs are 5-HT2A
receptor agonists and, as such, are expected to downregulate 5-HT2A
receptors (Pranzatelli, 1991
A number of animal studies showed that chronic 5-HT depletion leads to upregulation of 5-HT2A
receptors, supporting the hypothesis that 5-HT2A
receptor upregulation observed in this study might be secondary to sustained 5-HT depletion (Cahir et al, 2007
; Heal et al, 1985
). The higher [11
C]MDL 100907 binding was observed in the neocortex, that is, in the same region where SERT density was lower. Moreover, within the cortex, a relationship (significant at trend level) was observed between lower [11
C]DASB binding and higher [11
C]MDL 100907 binding (), a relationship that might be driven by impact of axonal length of 5-HT neurons vulnerability to MDMA. Thus, the data converged to indicate the existence of an alteration in both presynaptic and postsynaptic 5-HT markers in the cortex, alterations consistent with a state of decreased 5-HT tone and in line with the animal data showing the vulnerability of cortical 5-HT terminals to repeated MDMA exposure. It remains unclear if the alterations observed in this study represent reversible functional adaptations, potentially irreversible neurotoxic changes, or some combination of both factors.
The result from this study confirms, in an independent cohort, that current MDMA exposure is associated with lower SERT availability in cortical but not subcortical regions. This study also reveals that upregulation of 5-HT2A
receptors is found in cortical areas of these subjects, suggesting the existence of a chronic state of lower 5-HT tone in these subjects. Together with the animal literature, the most direct interpretation of these studies is that repeated exposure to MDMA, even at moderate levels, leads to changes in serotonin parameters in the most vulnerable 5-HT neurons, that is, 5-HT neurons innervating the cortex. The reversibility of these changes upon sustained abstinence is suggested by several studies (Buchert et al, 2006
; Erritzoe et al, 2011
; Kish et al, 2010
; McCann et al, 2005
; Selvaraj et al, 2009
), supporting temporary downregulation of SERT and upregulation of 5-HT2A
in response to acute 5-HT depletion, but remains to be firmly established. The functional implication of these changes are unknown, but it is conceivable that alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain the MDMA-taking behavior.