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Randomized Controlled Trial
. 2015 Oct 15;78(8):554-62.
doi: 10.1016/j.biopsych.2013.12.015. Epub 2014 Jan 10.

The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured With Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity

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Free PMC article
Randomized Controlled Trial

The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured With Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity

Robin L Carhart-Harris et al. Biol Psychiatry. .
Free PMC article

Abstract

Background: The compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals.

Methods: In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level-dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week.

Results: Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects.

Conclusions: The MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug's characteristic subjective effects arise from its modulation of spontaneous brain activity.

Keywords: 5-HT; Amygdala; Hippocampus; MDMA; PTSD; Serotonin; fMRI.

Figures

Figure 1
Figure 1
Schematic showing scanning protocol. Placebo (vitamin C) or 3,4-methylenedioxymethamphetamine (MDMA) hydrochloride (100 mg) was ingested at time zero, and the first arterial spin labeling scan performed 50 min later. This was a repeated measures design; the two scans (placebo and MDMA) were performed 1 week apart, and the scan order was counterbalanced so that half of the volunteers received MDMA for the first scan, and half received MDMA for the second scan. ASL, arterial spin labeling; BOLD, blood oxygen level–dependent.
Figure 2
Figure 2
Subjective effects of 3,4-methylenedioxymethamphetamine (MDMA). There were 29 items rated 4 hours after drug administration. Participants were instructed to complete the items with reference to the peak drug effects (where applicable). The items marked with an asterisk were rated significantly higher after MDMA than placebo (p < .001, Bonferroni correction for multiple comparisons). The mean ratings for 25 participants are shown plus the positive standard errors from the mean (SE).
Figure 3
Figure 3
Decreases in cerebral blood flow (CBF) after administration of 3,4-methylenedioxymethamphetamine (MDMA). (A) Regions of significantly less CBF after MDMA administration (scans 1 and 2) vs. placebo (scans 1 and 2) are displayed. These images are cluster-corrected giving a whole-brain corrected statistical threshold of p < .05. See Supplement 1 for additional slices. (B,C) Decreased right amygdala and hippocampal CBF predicts intense subjective effects after MDMA. Values on the x-axis are ratings from the first and second arterial spin labeling scans after MDMA administration. A corrected p value of < .005 was used. The decreases in CBF after MDMA administration versus placebo increase in magnitude from left to right. The greater the decreases in CBF in the amygdalae and hippocampi after MDMA administration, the more intense were the drug’s subjective effects. ASL, arterial spin labeling; hipp, hippocampus.
Figure 4
Figure 4
Effect of 3,4-methylenedioxymethamphetamine (MDMA) on resting state functional connectivity (RSFC). (A) Changes in ventromedial prefrontal cortex (vmPFC) RSFC. (B) Changes in hippocampal RSFC after MDMA administration. (C) Changes in amygdala RSFC after MDMA administration. Increases in RSFC are shown in yellow-orange, and decreases in RSFC are shown in blue. All seeds are shown in red. The blue lines on the axial and sagittal slices on the far right indicate the planar position of the preceding slices. All images were cluster-corrected, z = 2.3, p < .05.

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