Healthy VolunteersNeuroimaging & Brain MeasuresMDMA

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

This double-blind, placebo-controlled, balanced-order, within-subjects study (n=25) investigated how the subjective effects of MDMA are related to its neural effects .fMRI scans during MDMA use showed changes in cerebral blood flow in the right medial temporal lobe, thalamus, inferior visual cortex, somatosensory cortex, right amygdala and hippocampus, as well as decreased resting-state functional connectivity (RSFC) between midline cortical regions, the medial prefrontal cortex, and the medial temporal lobe, and increased RSFC between the amygdala and hippocampus.

Authors

  • Robin Carhart-Harris
  • David Nutt
  • Leor Roseman

Published

Biological Psychiatry
individual Study

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.

Unlocked with Blossom Pro

Research Summary of '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'

Editorial

βBlossom's Take

This study is useful because it moves MDMA from broad claims about sociability to actual brain measures, including cerebral blood flow and resting-state connectivity. The pattern in medial temporal and midline cortical regions gives later work a concrete neuroimaging reference for MDMA's acute social and affective effects.

Cited By (36)

Papers in Blossom that reference this study

Psychedelic medicine: mechanisms, evidence, and translation to practice

Jacobs, E., Zahid, Z., Hinkle, J. et al. · BMJ (2026)

3 cited
Self-compassion mediates treatment effects in MDMA-assisted therapy for posttraumatic stress disorder

Agin-Liebes, G. I., Zeifman, R. J., Mitchell, J. · European Journal of Psychotraumatology (2025)

10 cited
1 cited
The conceptual framework for the therapeutic approach used in phase 3 trials of MDMA-assisted therapy for PTSD

O'Donnell, K., Okano, L., Alpert, M. et al. · Frontiers in Psychology (2024)

23 cited
Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences

Zeifman, R. J., Kettner, H., Pagni, B. A. et al. · Scientific Reports (2023)

30 cited
Increased low-frequency brain responses to music after psilocybin therapy for depression

Wall, M. B., Lam, C., Ertl, N. et al. · Journal of Affective Disorders (2023)

35 cited
Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder

Singleton, S. P., Wang, J. B., Mithoefer, A. T. et al. · Frontiers in Psychiatry (2023)

48 cited
Show all 36 papers
42 cited
A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults

Maples-Keller, J. L., Norrholm, S. D., Burton, M. et al. · Journal of Psychopharmacology (2022)

52 cited
Debunking the myth of ‘Blue Mondays’: No evidence of affect drop after taking clinical MDMA

Sessa, B., Aday, J. S., Curran, H. V. et al. · Journal of Psychopharmacology (2021)

18 cited
A Systematic Review of the MDMA Model to Address Social Impairment in Autism

Chaliha, D., Mamo, J. C., Albrecht, M. et al. · Current Neuropharmacology (2021)

5 cited
Psilocybin and MDMA for the treatment of trauma-related psychopathology

Bird, C. I. V., Modlin, N. L., Rucker, J. · International Review of Psychiatry (2021)

76 cited
Reviewing the potential of psychedelics for the treatment of PTSD

Krediet, E., Bostoen, T., Breeksema, J. J. et al. · International Journal of Neuropsychopharmacology (2020)

257 cited
A proof-of-principle study of the short-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on tinnitus and neural connectivity

Searchfield, G. D., Poppe, T. N. E. R., Durai, M. et al. · International Journal of Neuroscience (2020)

8 cited
Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline

Feduccia, A. A., Jerome, L., Yazar-Klosinski, B. et al. · Frontiers in Psychiatry (2019)

170 cited
Psychedelic drugs-a new era in psychiatry?

Nutt, D. J. · Dialogues in Clinical Neuroscience (2019)

131 cited
Combining Cognitive-Behavioral Conjoint Therapy for PTSD with 3,4-Methylenedioxymethamphetamine (MDMA): A Case Example

Wagner, A. C., Mithoefer, M. C., Mithoefer, A. T. et al. · Journal of Psychoactive Drugs (2019)

91 cited
MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms?

Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)

210 cited
Psilocybin and MDMA reduce costly punishment in the Ultimatum Game

Gabay, A. S., Carhart-Harris, R. L., Mazibuko, N. et al. · Scientific Reports (2018)

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Carhart-Harris, R. L., Roseman, L., Bolstridge, M. et al. · Scientific Reports (2017)

585 cited
Serotonin and brain function: a tale of two receptors

Carhart-Harris, R. L., Nutt, D. J. · Journal of Psychopharmacology (2017)

727 cited
Ego-dissolution and psychedelics: validation of the ego-dissolution inventory (EDI)

Nour, M. R., Evans, J., Nutt, D. J. et al. · Frontiers in Human Neuroscience (2016)

475 cited
Neural correlates of the LSD experience revealed by multimodal neuroimaging

Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)

875 cited
3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

Young, M. B., Andero, R., Ressler, K. J. et al. · Translational Psychiatry (2015)

134 cited
Making a medicine out of MDMA

Sessa, B., Nutt, D. J. · British Journal of Psychiatry (2015)

36 cited
The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

Roseman, L., Leech, R., Feilding, A. et al. · Frontiers in Human Neuroscience (2014)

291 cited