Our group 31
and others 32,33 ,33 ,34
have used proton magnetic resonance spectroscopy (MRS) to assay for MDMA-induced effects in human MDMA-users. To date, MRS has been used mainly to measure N-acetylaspartate (NAA) and myoinositol (MI) concentrations in MDMA users. NAA, as a putative neuronal marker, may have utility in assaying MDMA effects if MDMA produces changes in neurona25
l size or metabolic viability 35 ,36
. As depicted in , lower left, NAA (in green) is present in pyramidal and other cortical neurons and might be expected to decrease in the post-MDMA state if there is neuronal damage or neuronal shrinkage. Other potential causes for reduced NAA, including possible loss of fine diameter 5-HTaxons or scattered neuronal necrosis 37
do not appear likely to contribute to NAA changes detected by MRS because current methods have employed fairly large volumes of interest and thus might not detect loss of small numbers of neurons or the small amount of NAA contained in fine-diameter serotonergic axons. Alternatively, it is possible that NAA metabolic/catabolic processes may be modulated by MDMA in an unknown manner. MI, as a putative glial marker 38 ,39
(, magenta glial cell), seems less likely to emerge as a specific marker of brain change in MDMA users. MI is depicted in as a glial marker that might increase if there is glial proliferation or hypertrophy following MDMA exposure. MI is widespread in brain glia and does show alterations with gross brain damage such as in demyelinating disorders 38
, but there is little evidence to support gliosis following MDMA exposure 14
As reviewed in detail elsewhere 7
, findings to date from MRS have not revealed a consistent pattern of findings. Assays of prefrontal, temporal, and parieto-occipital NAA and MI have revealed conflicting findings 32,33
. These groups studied subjects having relatively high levels of MDMA and polydrug exposure, which may have contributed to disparate findings. Using high field MRS at 4.0 Tesla (which offers increased SNR), we recently examined NAA and MI concentrations in the occipital cortex of MDMA users having fairly low levels of MDMA and polydrug use 31
and found no differences, or even a clear trend for an association of MDMA use with metabolite levels. However, if subtle effects exist, this study would have been underpowered in detecting those changes.
One possibility for negative or divergent results from MRS studies is that MDMA use may produce regional brain changes that are not detected if MRS volumes of interest are placed in regions unaffected my MDMA exposure. Based on this concern, we have begun studying NAA and MI using volumes of interest based upon our earlier findings (Cowan et al.
. 43) of reduced brain gray matter concentration in MDMA users. We reasoned that areas having reduced brain gray matter concentration would be the most likely regions to yield evidence for altered NAA. Applying this approach to a group of MDMA users not overlapping with those studied in the original VBM report, we used proton MRS at 3.0 Tesla to examine NAA and MI using volumes of interest placed in left Brodmann Areas 45, 21, and 18 in MDMA users abstinent from all drug or alcohol for at least 2 weeks. These regions of interest were not only based on our earlier VBM findings 24
but also overlap with brain regions potentially associated with verbal memory deficits reported in cognitive studies of MDMA users 40
. Our preliminary findings in a small sample subset do not suggest an association between MDMA use and metabolite ratios, nor for use of alcohol, cannabis, or methamphetamine and metabolite ratios in this group. This early negative finding may be due to the absence of drug effects, mixed effects from different drugs, or limitations of the sample size or methodology.