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Elife. 2018 Oct 25;7. pii: e35082. doi: 10.7554/eLife.35082.

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.

Author information

1
Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Zurich, Switzerland.
2
Department of Psychiatry, Yale University School of Medicine, New Haven, United States.
3
Department of Physics, Yale University, New Haven, United States.
4
Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Zurich, Switzerland.
5
Mind and Brain Lab, Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
6
Department of Neuroscience, Yale University School of Medicine, New Haven, United States.
#
Contributed equally

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 study (ClinicalTrials.gov, NCT02451072) during 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.

FINDINGS:

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.

CONCLUSION:

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:

Swiss National Science Foundation (SNSF, P2ZHP1_161626, KHP), the Swiss Neuromatrix Foundation (2015 - 0103, FXV), the Usona Institute (2015 - 2056, FXV), the NIH (R01MH112746, JDM; DP5OD012109, AA; R01MH108590, AA), the NIAA ( P50AA012870-16, AA & JHK), the NARSAD Independent Investigator Grant (AA), the Yale CTSA grant (UL1TR000142 Pilot Award, AA), and the Slovenian Research Agency (ARRS J7-6829 & ARRS J7-8275, GR).

KEYWORDS:

LSD; brain; fMRI; functional connectivity; human; human biology; medicine; neuroscience; psychedelics; serotonin

PMID:
30355445
PMCID:
PMC6202055
DOI:
10.7554/eLife.35082
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

KP, JB, JJ, CS, BA, PS, ES, JK, FV No competing interests declared, GR consults for and holds equity with Blackthorn Therapeutics. JM John D Murray: consults for and holds equity with Blackthorn Therapeutics. AA Alan Anticevic: consults for and holds equity with Blackthorn Therapeutics.

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