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Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin
Open accessAbstract
There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.
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![Fig. 2 Raincloud plots displaying metabolite concentrations in the mPFC and the hippocampus, which demonstrated significant differences between treatment groups. a glutamate in the mPFC, b NAA in the mPFC, c glutamate in the hippocampus, d GABA in the mPFC. The plot consists of a probability density plot, a boxplot, and raw data points. In the boxplot, the line dividing the box represents the median of the data, the ends represent the upper/lower quartiles, and the extreme lines represent the highest and lowest values excluding outliers. The code for raincloud plot visualization has been adapted from Allen et al. [99].](/paper-figures/c830fa3cb891411e99e26af3030e1d35/me-myself-bye-regional-alterations-in-glutamate-and-the-experience-of-ego-figure-2.jpg)

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“Consequently, in this state, individuals may more readily engage with their cognitive beliefs and emotional states with enhanced detachment and decentration, potentially leading to therapeutic outcomes [42, 43].”
From Mindfulness meditation and psychedelics: potential synergies and commonalities (2023) · cites this paper as [42]
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“The potential of classic psychedelics to alter glutamate in the human cortex, albeit in a region-dependent manner, has been demonstrated (92).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [92]
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Citations
Cites
A default mode of brain function
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.676 · Cited by 12,190
Correspondence of the brain's functional architecture during activation and rest
Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, C. E., Filippini, N., Watkins, K. E., Toro, R., Laird, A. R., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905267106 · Cited by 5,150
Conn : A Functional Connectivity Toolbox for Correlated and Anticorrelated Brain Networks
Whitfield-Gabrieli, S., & Nieto-Castanon, A. (2012) · Brain Connectivity · doi:10.1089/brain.2012.0073 · Cited by 4,885
A method for making group inferences from functional MRI data using independent component analysis
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Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116675513 · Cited by 2,201 · cited 2×
“A paradoxical effect of serotonergic psychedelics is that acutely they have been found to increase feelings of anxiety [6, 78], whereas clinical trials with psychedelic drugs suggest long-term anxiety relief in patients [11, 12, 14].”
BackgroundNichols, D. E. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011478 · Cited by 1,762
Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0457-5 · Cited by 1,684
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M. J., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., et al. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(16)30065-7 · Cited by 1,540
Self-citationBunney, W. E., Hippius, H., Laakmann, G., & Schmauß, M. (1990) · Springer eBooks · doi:10.1007/978-3-642-74034-3 · Cited by 1,523
A Baseline for the Multivariate Comparison of Resting-State Networks
Allen, E. A., Erhardt, E. B., Damaraju, E., Gruner, W. E., Segall, J. M., Silva, R. F., Havlíček, M., Rachakonda, S., Fries, J. F., Kalyanam, R., et al. (2011) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2011.00002 · Cited by 1,329
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Towards an understanding of psychedelic-induced neuroplasticity
Calder, A. E., & Hasler, G. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01389-z · Cited by 313
Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Aleksandrova, L. R., & Phillips, A. G. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.08.003 · Cited by 276
Psilocybin desynchronizes the human brain
Siegel, J. S., Subramanian, S., Perry, D., Kay, B. P., Gordon, E. M., Laumann, T. O., Reneau, T. R., Metcalf, N. V., Chacko, R. V., Gratton, C., et al. (2024) · Nature · doi:10.1038/s41586-024-07624-5 · Cited by 308
de Vos, C. M. H., Mason, N. L., & Kuypers, K. P. C. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.724606 · Cited by 269
Self-citationDefault Mode Network Modulation by Psychedelics: A Systematic Review
Gattuso, J. J., Perkins, D., Ruffell, S., Lawrence, A. J., Hoyer, D., Jacobson, L. H., Timmermann, C., Castle, D., Rossell, S. L., Downey, L. A., et al. (2023) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac074 · Cited by 256
Metadata
- Authors
- Mason, N. L., Kuypers, K. P. C., Müller, F., Reckweg, J., Tse, D. H. Y., Toennes, S. W., Hutten, N. R. P. W., Jansen, J. F. A., Stiers, P., Feilding, A., & Ramaekers, J. G.
- Affiliations
- Maastricht University (NL)
- University of Basel (CH)
- Goethe University Frankfurt (DE)
- Maastricht University Medical Centre (NL)
- Beckley Foundation (GB)
- Corresponding author
- Mason, N. L.
- Ramaekers, J. G.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2020-05-23
- Volume
- 45
- Issue
- 12
- Pages
- 2003-2011
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC7547711
- OpenAlex
- W3027590463
- Cited by
- 258
- References
- 102
- Citations by year
- 2026: 36 · 2025: 41 · 2024: 40 · 2023: 62 · 2022: 42 · 2021: 32 · 2020: 5
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Beckley Foundation
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Social Psychology › Paranormal Experiences and Beliefs
- Keywords
- psilocybin, glutamate, ego dissolution, self-experience, medial prefrontal cortex, hippocampus, subjective experience, psychedelics, depression, ultra-high field MRI
- MeSH terms
- Ego, Hallucinogens, Humans, Psilocybin, Solubility, Glutamic Acid
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