Purpose: Brain imaging, neuropsychological, "The aim of this study was to characterize acute MDMA effects in terms of regional cerebral changes in brain [EEG] activity compared to placebo." (p. 153). Specific hypotheses tested - that changes in EEG activity would be observed after MDMA administration (compared with placebo) and that MDMA would have an EEG spectral band profile similar to profiles of 5-HT, DA and NE agonists (comparisons made with findings drawn from other studies).

Design: Randomized double-blind within-subjects design, with drug treatment (placebo or MDMA) as a within-subjects factor. Each participant underwent 1 placebo and 1 MDMA session (receiving 1.7 mg / kg MDMA p.o.), with sessions scheduled approximately one month apart.

Subjects: 16 MDMA-na#&239;ve subjects (6 women, 10 men, mean age 26 ± 2.5 years) recruited from university students and hospital staff.

Criteria for inclusion - Lack of major medical or psychiatric illness as assessed through medical history, psychiatric interview, physical exam, ECG and blood analysis. Lack of history of psychiatric illness for self and 1st-degree relatives, lack of any psychiatric, psychopharmacological or psychotherapeutic treatment, and no history of substance abuse.

Measures: EEG - Measured via LORETA performed 2 h after drug administration, using a 32-channel headbox. Participants were lying down, and EEG was measured under eyes open and eyes-closed conditions, with each condition maintained for at least 3 min. 2-second artifact-free epochs were used for analysis. EEG was measured in 7 spectral frequency bands: Delta (1.5-6 Hz), Theta (6.5-8 Hz), Alpha1 (8.5-10 Hz), Alpha2 (10.5-12 Hz), Beta1 (12.5-18 Hz), beta2 (18.5-21 Hz) and Beta3 (21.5-30 Hz). A three-shell spherical head model registered to Talairach space was used to create LORETA images. 3D LORETA images were computed for each subject, with 4 images computed overall, eyes open-placebo, eyes closed-placebo, eyes open-MDMA and eyes closed-MDMA.

Mood - Measured via AM (reportedly administered 4 h after placebo or MDMA administration in companion paper, Gamma et al 2000).

Alterations in Consciousness - Measured via ASC (reportedly administered 4 h after placebo or drug administration in companion paper).

Analyses: Imaging - LORETA images were analyzed via statistical non-parametric mapping method (SnPM). Images compared with voxel by voxel t-tests, using one image per subject, frequency band and visual input condition (eyes open versus shut), and drug condition (MDMA versus placebo), with t-tests used to locate areas of statistically significant difference. A second non-parametric analysis assessed significance of activity based on spatial extent.

Mood - Responses to AM analyzed via 2-way repeated-measures ANOVA, with condition (placebo vs. 1.7 mg/kg MDMA) as one within-subjects factor and each AM subscale (6 scales) as a repeated measure (within-subjects factor). Post-hoc comparisons performed via Tukey's test, with p. at 0.05.

Alterations in Consciousness - Responses to the ASC were analyzed via 2-way repeated-measures ANOVA, with condition (placebo versus 1.7 mg/kg MDMA) as 1 within-subjects factor and subscale (3 scales) as another repeated measure. Post-hoc comparisons performed via Tukey's test and p. at 0.05.

Results: Imaging, General - After removing epochs with artifacts, the final sample for the eyes open condition was 12 / 16 and 14 / 16 in eyes closed. Comparing LORETA spectral band power maps across treatments (MDMA vs. placebo), significant differences were found between the two drug treatments in all 7 spectral bands and in both visual input conditions. (Authors only report further analysis of spectral bands where statistical difference greater than p. = 0.01). Eyes Open - EEG showed decrease in Delta, Theta, Alpha1 and Alpha2 after MDMA, as compared with placebo. Beta1, Beta2 and Beta3 increased after MDMA, but there were regions of decreased Beta1 and Beta2. Eyes Closed - Delta, Theta and Alpha1 were all comparatively decreased after MDMA, as compared with placebo, but there was no statistically significant decrease in Alpha2 after MDMA in the eyes closed condition. There were increases in Beta1, Beta2 and Beta3 after MDMA in the eyes closed condition.

Imaging, Regional - (All comparisons phrased as changes from placebo.)

Eyes Open - Decrease in Delta greatest in left pre-motor cortex. Decreases in Theta was greatest at the posterior cingulate, but involved other areas as well ("global"). Alpha1 was maximally decreased in the parietal and occipital cortex, but was maximally decreased at posterior cingulate. Alpha2 was decreased in R parietal cortex, and declined bilaterally in temporo-occipital cortex extending to the hippocampal formation, with maximal decrease in the posterior cingulate. Beta1 frequency was increased in R orbitofrontal area and anterior temporal and posterior orbitofrontal cortex, and increased Beta1 extended into the insula and posterior frontal lobe. Beta2 was decreased in the parietal cortex, but was increased bilaterally at anterior temporal, orbitofrontal, prefrontal and fusiform cortex, with maximal Beta3 increase at the temporal gyrus (term used in paper).

Eyes Closed - Delta frequency was bilaterally decreased in the cingulate and precentral gyrus. Theta decreased globally and bilaterally, with decreased activity centered at the posterior cingulate, including entire cingulate, parietal cortex, posterior temporal regions and R occipital, fusiform and hippocampal regions. Alpha1 was bilaterally decreased in the frontal cortex and entire cingulate. Beta1 was increased in R anterior temporal region and in posterior orbitofrontal cortex. A bilateral increase in Beta2 was found at anterior temporal and posterior orbitofrontal cortex, extending to R insular cortex. Beta3 increased bilaterally in anterior superior temporal gyrus, with increased Beta3 at L inferior temporal and parahippocampal regions and at R subcallosal gyrus.

Mood - When compared to placebo, MDMA significantly elevated scores on well-being, extroversion, emotional excitability and anxiety. Both the heightened mood and the self-confidence aspect of "well-being" were significantly higher after MDMA. Extroversion was reflected in higher scores for sociability, talkativeness, outgoingness and friendliness. Anxiety scores increased due to elevated "thoughtfulness / contemplation" scores, and neither apprehension nor dejection.

Alterations in Consciousness - All ASC scale scores (OB, VR and AED) were increased after MDMA, as compared to placebo. Increase in OB after MDMA largely due to increase in positive mood, positive derealization and positive depersonalization. VR increase largely due to increased visual illusions and increased tactile awareness. AED increase mainly due to increases in thought disorder and signs of loss of body control. Participants did not report greater psychomotor drive after MDMA, compared with placebo.

Overall Effects: A dose of 1.7 mg/kg MDMA administered human volunteers altered EEG spectral power across all 7 spectral bands measured (Delta, Theta, Alpha1, Alpha2, Beta1, Beta2 and Beta3). Overall, MDMA produced decreased delta, theta, alpha1 and alpha2, and increased in Beta1, Beta2 and Beta3, with some region-specific decrease in Beta2. The MDMA-induced changes seen in the eyes-open condition were similar to the changes seen in an eyes-closed condition, though there was no decrease in Alpha3 in the eyes-closed condition. There were region-specific alterations in spectral band power, with many MDMA-induced decreases or increases in spectral band centered over the cingulate (either entire cingulate, anterior cingulate or posterior cingulate). Changes tended to be bilateral, but some were localized to one hemisphere (e.g. maximal decrease delta in eyes open in left premotor gyrus, decreased eyes open alpha2 in R parietal region, increased Beta1 in R orbitofrontal and anterior temporal cortex). As has been reported in other papers, MDMA produced a state of elevated positive mood, greater extroversion, greater emotional excitability, and a moderate increase in anxiety namely due to increased contemplativeness. Participants reported increased scores on all three scales of the ASC, including positive mood associated with positively experienced derealization and depersonalization, perceptual changes and anxiety over ego dissolution. The authors' hypotheses were partially confirmed. As predicted, MDMA produced changes in spectral band power. While a hypothesized similarity between the changes in spectral band power seen after MDMA were similar to LORETA findings for serotonergic, dopaminergic and noradrenergic drugs reported in other studies, the original hypothesis did not specify the exact nature of these similarities. It is surprising, for instance, that the LORETA profile of the acute effects of MDMA bears more similarity to the LORETA profile of noradrenergic drugs, and that the acute effects of SSRIs produce nearly opposite changes in spectral band power.

Adverse Effects: None reported in this paper beyond moderate increase in AM and ASC scales of anxiety and higher scores on the AED sub-scale of the ASC for "thought disorder" and "loss of bodily control."

Comments: To date, this paper is the first to report on LORETA spectral band images taken during the acute effects of MDMA in humans. The authors also used LORETA images to compare spectral power in drug-free ecstasy users and non-users in an earlier paper. Perhaps because the technique is relatively new and because there are little or no studies in non-human animals employing the same technique, it is difficult to ascertain the significance of these findings. However, the authors compare their findings concerning changes in spectral band after MDMA with changes seen after other drugs. It appears that spectral power produced by the acute effects of MDMA were similar to those produced by fenfluramine and tandamine, while being not as similar to LORETA images of amphetamines and being opposite to the effects of acutely administered SSRIs. As with most imaging studies, the conclusions of this study may be hampered by small sample size. The findings in this paper may prove interesting as one of a growing number of studies using LORETA EEG as a way of imaging brain activity.