Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor
Open accessPublished version of a preprint
Abstract
Background: Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown. Methods: We therefore conducted a double-blind, randomized, counterbalanced, cross-over studyduring which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps. Results: LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans. Conclusions: Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoints the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics. Funding: Funded by the Swiss National Science Foundation, the Swiss Neuromatrix Foundation, the Usona Institute, the NIH, the NIAA, the NARSAD Independent Investigator Grant, the Yale CTSA grant, and the Slovenian Research Agency. Clinical trial number: NCT02451072 .
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Mystical-type experiences could simply be an epiphenomenon associated with 5-HT2A receptor activation.
“mystical-type experiences could simply be an epiphenomenon associated with 5-HT2A receptor activation (227, 228)”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [228]
The Results assess spiritual experience among LSD’s subjective effects, and the Discussion (Time-dependent effects of LSD; no page given) reports that ketanserin blocked subjective effects, which the authors attribute to 5-HT2A receptor stimulation. This supports an association, but the paper does not establish that mystical-type experiences are merely an epiphenomenon. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDifferences in insula-thalamus connectivity have been reported in meditators compared with nonmeditators, and after psychopharmacological administration of lysergic acid diethylamide.
“differences in insula–thalamus connectivity have been reported in meditators compared with nonmeditators, and after psychopharmacological administration of lysergic acid diethylamide, which possesses robust anti-depressant and anxiolytic properties.46,47”
From Distinct and shared therapeutic neural mechanisms of mindfulness-based and social support stress reduction groups in adults with autism spectrum disorder (2023) · cites this paper as [46]
The Results section (page unavailable) reports changes in thalamic connectivity after LSD, and the Discussion identifies LSD-related hypoconnectivity in the insula. The passages do not specifically establish a change in connectivity between the insula and thalamus. The meditator comparison is not a finding of this LSD study. (LLM, conf=0.82)
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References 86 · Cited by 390
Research works printed but not linked: 1
- Glasser MF Coalson TS Bijsterbosch JD Harrison SJ Harms MP Anticevic A 2017 Using temporal ICA to selectively remove global noise while preserving global signal in functional MRI data bioRxiv 10.1101/193862 PMC6237431 29753843 · DOI
- Authors
- Preller, K. H., Burt, J. B., Ji, J. L., Schleifer, C. H., Adkinson, B. D., Stämpfli, P., Seifritz, E., Repovs, G., Krystal, J. H., Murray, J. D., Vollenweider, F. X., & Anticevic, A.
- Affiliations
- University of Zurich (CH)
- Yale University (US)
- University Hospital Zurich (CH)
- Mind and Brain Lab, Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
- Corresponding author
- Preller, Katrin H
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-10-25
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6202055
- OpenAlex
- W2950564037
- Cited by
- 390
- References
- 86
- Citations by year
- 2026: 50 · 2025: 55 · 2024: 58 · 2023: 67 · 2022: 55 · 2021: 47 · 2020: 30 · 2019: 22 · 2018: 4 · 2017: 1
- FWCI
- 30.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P2ZHP1_161626)
- Javna Agencija za Raziskovalno Dejavnost RS (ARRS J7-6829, ARRS J7-8275)
- National Institute on Alcohol Abuse and Alcoholism (P50AA012870-16)
- National Institutes of Health (R01MH112746, DP5OD012109, R01MH108590)
- Swiss Neuromatrix Foundation (2015-0103)
- Usona Institute (2015-2056)
- National Alliance for Research on Schizophrenia and Depression (Independent Investigator Grant)
- Yale CTSA grant (UL1TR000142 Pilot Award)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Keywords
- lysergic acid diethylamide, LSD, 5-HT2A receptor, ketanserin, altered states of consciousness, resting-state functional connectivity, thalamic connectivity, cortical gene expression, serotonin receptors
- MeSH terms
- Adult, Double-Blind Method, Female, Hallucinogens, Humans, Lysergic Acid Diethylamide, Male, Neural Pathways, Placebos, Thalamus, Cross-Over Studies, Young Adult, Serotonin 5-HT2 Receptor Antagonists, Healthy Volunteers
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