Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor
Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji, Charles Schleifer, Brendan Adkinson, Philipp Stämpfli, Erich Seifritz, Grega Repovš, John H. Krystal, John D. Murray, Franz X. Vollenweider, Alan Anticevic
eLife October 25, 2018 DOI: 10.7554/elife.35082 via OpenAlex
Summary
AI-generated from the abstractLysergic acid diethylamide (LSD) reduces associative brain connectivity while increasing sensory-somatomotor and thalamic connectivity. These neural effects, along with the subjective experience, are fully blocked by ketanserin, a selective 5-HT2A receptor antagonist. The spatial pattern of LSD's effects across the brain matches the distribution of 5-HT2A receptor gene expression in humans. These results strongly implicate the 5-HT2A receptor in LSD's neuropharmacology, informing the neurobiology of psychedelics and guiding development of psychedelic-based therapeutics.
Study at a glance
| Characteristics | Double-blind, randomized, counterbalanced, cross-over study Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Healthy human participants |
| Interventions | LSD Ketanserin |
| Dose | 100 µg |
| Topics | Serotonin |
| Keywords | Ketanserin Neuroscience Neuropharmacology Psychology Agonist |
| Citations | 416 |
| Registration | NCT02451072 |
| Key finding | The 5-HT2A receptor is critical for LSD's subjective and neural effects, as ketanserin fully blocked both. |
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 .