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

• DOI: 10.7554/elife.35082
• Publication Date: 2018-10-25T11:00:50Z
• Authors: Katrin H Preller; Joshua B Burt; Jie Lisa Ji; Charles H Schleifer; Brendan D Adkinson; Philipp Stämpfli; Erich Seifritz; Grega Repovs; John H Krystal; John D Murray; Franz X Vollenweider; Alan Anticevic
• Keywords: Adult; Male; QH301-705.5; brain; Science; 610 Medicine & health; LSD; Placebos; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Double-Blind Method; Thalamus; 1300 General Biochemistry, Genetics and Molecular Biology; 2400 General Immunology and Microbiology; Neural Pathways; Humans; Biology (General); Cross-Over Studies; functional connectivity; fMRI; Q; R; 2800 General Neuroscience; psychedelics; Healthy Volunteers; serotonin; 3. Good health; Lysergic Acid Diethylamide; 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics; Hallucinogens; Serotonin 5-HT2 Receptor Antagonists; Medicine; Female

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.