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., 2015

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, Kevin Murphy, Robert Leech, David Erritzoe, Matthew B. Wall,
Bart Ferguson, Luke T.J. Williams, Leor Roseman, Stefan Brugger, Ineke De Meer,
Mark Tanner, Robin Tyacke, Kim Wolff, Ajun Sethi, Michael A.P. Bloomfield, Tim M. Williams,
Mark Bolstridge, Lorna Stewart, Celia Morgan, Rexford D. Newbould, Amanda Feilding,
H. Val Curran, and David J. Nutt

Biological Psychiatry, 2015, 78, 554-562.



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 : Amygdala, 5-HT, fMRI, Hippocampus, MDMA, PTSD, Serotonin

The compound 3,4-methylenedioxymethamphetamine (MDMA) releases serotonin (5-hydroxy-tryptamine [5-HT]), dopamine, and norepinephrine (1). It is also a popular recreational drug that is valued by users because of its acute prosocial and euphoretic properties (2). Although MDMA has been administered in human research on numerous occasions (3–5), few studies have investigated its acute effects on brain function using functional magnetic resonance imaging (fMRI) (6–8) or other neuroimaging modalities (9–11).

The compound MDMA has a relatively unique profile of subjective effects, described as a hybrid between a stimulant and psychedelic (12). It acts at dopamine, norepinephrine, and 5-HT transporters to inhibit reuptake and stimulate release; however, the greater action of MDMA at the serotonin transporter
differentiates it from most other stimulants (13) and accounts for much, but not all, of its euphoretic effects (14,15). Although the pharmacology of MDMA is reasonably well understood, little is known about its effects on global brain function. More recently, MDMA has been investigated as a potential adjunct to psychotherapy in the treatment of posttraumatic stress disorder (PTSD), with positive, albeit preliminary, outcomes (16,17).

Despite significant developments in resting state fMRI in recent years (18), there have been no resting state fMRI studies on the acute effects of MDMA. In the present study, we combined arterial spin labeling (ASL) and resting state functional connectivity (RSFC) to address this knowledge gap. The magnetic resonance imaging technique ASL provides a quantitative measure of cerebral blood flow (CBF) or perfusion (19), and RSFC measures functional coupling between spatially distributed brain regions via spontaneous fluctuations in the blood oxygen level–dependent (BOLD) signal (20). Combining these complementary techniques can yield important new information on how a drug alters brain activity to produce its characteristic subjective effects (21). Given the recognized acute prosocial and positive mood effects of MDMA (6,22), we predicted changes in CBF and RSFC in brain systems implicated in social and affective processing—limbic structures and the medial prefrontal cortex (mPFC) (23,24). On this basis, three regions (i.e., ventromedialprefrontal cortex [vmPFC], bilateral hippocampi, and amygdalae) were selected for seed-based RSFC analyses (20).

Supporting the importance of this research is: 1) the relative dearth of human functional neuroimaging data on what is one of the most popular drugs of potential misuse (25); 2) the ability of MDMA to produce an acute state of euphoria and the poor understanding of the neural underpinnings of such states (26); 3) the ability of MDMA to produce marked 5-HT release (13), supporting its utility in serotoninergic challenge (27); and 4) preliminary evidence for the potential of MDMA as a therapeutic agent (17).