Dissociable effects of LSD and MDMA on striato-cortical connectivity in healthy subjects
In healthy volunteers, acute MDMA and LSD did not alter within-network connectivity of associative, limbic or sensorimotor striatal seeds but produced distinct striato‑cortical changes: MDMA reduced limbic striatum–amygdala coupling, while LSD increased associative striatum connectivity with frontal, sensorimotor and visual cortices. These drug-specific effects mainly occurred outside standard striatal networks, consistent with reduced network modularity and increased cross‑network connectivity under psychedelics.
Authors
- Robin Carhart-Harris
- David Nutt
- Leor Roseman
Published
Abstract
Introduction
Lysergic acid diethylamide (LSD) and 3,4-Methylenedioxymethamphetamine (MDMA) are widely used psychoactive drugs and their potential use in psychiatric medicine is currently generating interest. The mechanism by which these drugs may assist recovery in addiction, mood disorders and post-traumatic stress disorder (PTSD) is still not well understood. Most investigations of the effects of these drugs on brain activity have focussed on cortical resting-state networks, however the striatum is a key reward and motivation hub of the brain and aberrant striatal processing may be part of the pathophysiology of these disorders. Consequently, we investigated striatal connectivity following acute MDMA and LSD administration.
Method
Resting-state fMRI (rs-fMRI) data were acquired, and seed-voxel functional connectivity analyses were used with the striatum subdivided into three seed regions: the associative, limbic, and sensorimotor striatum. Within-network connectivity was measured using group mean network maps and whole-brain connectivity (seed-to-voxel) was also examined.
Results
Neither MDMA nor LSD significantly changed within-network connectivity of any of the three striatal seed regions. However, striatal connectivity with other brain regions was significantly altered with both MDMA and LSD. Most notably, MDMA reduced connectivity between the limbic striatum and the amygdala, while LSD increased connectivity between the associative striatum and the frontal, sensorimotor, and visual cortices.
Conclusion
Changes in connectivity were mostly observed outside the standard striatal networks, consistent with previous findings that psychedelics reduce network modularity or between-network segregation and increase connectivity across standard networks.
Research Summary of 'Dissociable effects of LSD and MDMA on striato-cortical connectivity in healthy subjects'
Introduction
Psychedelics such as lysergic acid diethylamide (LSD) and the entactogen MDMA are receiving renewed interest for potential psychiatric applications, but the neural mechanisms that might underlie therapeutic effects remain incompletely understood. Previous neuroimaging work has largely focused on cortical resting-state networks or on subcortical regions such as the thalamus, and has shown that classic psychedelics tend to increase global functional connectivity and reduce modularity. However, the striatum—a set of subcortical nuclei central to reward, motivation and many cortico‑striatal loops implicated in addiction, mood disorders and PTSD—has been relatively under-investigated despite its relevance to these conditions. Ertl and colleagues therefore set out to examine acute drug-induced changes in striatal functional connectivity using resting-state fMRI. The study re-analysed existing datasets from acute LSD and MDMA challenge studies, testing connectivity for three striatal subdivisions (associative, limbic and sensorimotor) both within their canonical networks and across the whole brain, to determine whether LSD and MDMA produce dissociable effects on striato-cortical coupling that might relate to their distinct phenomenology and putative therapeutic actions.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Ertl, N., Ashraf, I., Azizi, L., Roseman, L., Erritzoe, D., Nutt, D. J., Carhart-Harris, R. L., & Wall, M. B. (2025). Dissociable effects of LSD and MDMA on striato-cortical connectivity in healthy subjects. https://doi.org/10.1101/2025.02.07.637042
References (37)
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Aqil, M., Roseman, L. · Neuropharmacology (2022)
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Buot, A., Pallares, C., Oganesyan, A. et al. · Scientific Reports (2023)
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Show all 37 referencesShow fewer
Dyck, E. · Social History of Medicine (2006)
Family, N., Hendricks, P. S., Williams, L. T. J. et al. · Journal of Psychopharmacology (2022)
Forstmann, M., Yudkin, D. A., Prosser, A. M. B. et al. · PNAS (2020)
Fuentes, J. J., Fonseca, F., Elices, M. et al. · Frontiers in Psychiatry (2020)
Greer, G. R. · Journal of Psychoactive Drugs (1986)
Holze, F., Gasser, P., Müller, F. et al. · Biological Psychiatry (2023)
´dric, C., Hysek, M., Schmid, Y. et al. · Social Cognitive and Affective Neuroscience (2013)
Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)
Kaelen, M., Roseman, L., Kahan, J. et al. · European Neuropsychopharmacology (2016)
Spriggs, M. J., Murphy-Beiner, A., Murphy, R. et al. · Psychological Medicine (2022)
Liechti, M. E., Baumann, C., Gamma, A. et al. · Neuropsychopharmacology (2000)
Luppi, A. I., Carhart-Harris, R. L., Roseman, L. et al. · NeuroImage (2021)
Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
Netzer, O., Magal, N., Stern, Y. et al. · Biorxiv (2024)
Nichols, D. E. · Pharmacological Reviews (2016)
King, C., Nichols, D. E. · Nature Reviews Neuroscience (2013)
Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)
Preller, K. H., Burt, J. B., Adkinson, B. et al. · Biological Psychiatry (2020)
Roseman, L., Leech, R., Feilding, A. et al. · Frontiers in Human Neuroscience (2014)
Roseman, L., Sereno, M. I., Leech, R. et al. · Human Brain Mapping (2016)
Schmid, Y., Liechti, M. E. · Psychopharmacology (2017)
Schmid, Y., Schmidt, A., Müller, F. et al. · International Journal of Neuropsychopharmacology (2017)
Singleton, S. P., Wang, J. B., Mithoefer, A. T. et al. · Frontiers in Psychiatry (2023)
Tagliazucchi, E., Roseman, L., Kaelen, M. et al. · Current Biology (2016)
Timmermann, C., Roseman, L., Haridas, S. et al. · PNAS (2023)
Walpola, I. C., Nest, T., Leor, R. et al. · Neuropsychopharmacology (2017)
Zafar, R., Siegel, M., Harding, R. et al. · Frontiers in Psychiatry (2023)
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