Neuroimaging & Brain MeasuresHealthy VolunteersLSD

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

In a double‑blind, placebo‑controlled crossover in 24 healthy adults, LSD reduced associative but increased sensory‑somatomotor and thalamic global functional connectivity. These subjective and neural effects were fully blocked by the 5‑HT2A antagonist ketanserin and spatially matched cortical 5‑HT2A gene expression, implicating the 5‑HT2A receptor as the primary mediator of LSD’s brain connectivity changes.

Authors

  • Erich Seifritz
  • Katrin Preller
  • John Krystal

Published

eLife
individual Study

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

Introduction

Disorders of perception and thought contribute substantially to global disease burden, and psychedelic drugs provide pharmacologic probes for studying the neural mechanisms of consciousness. Preclinical and early human work indicate that lysergic acid diethylamide (LSD) acts at multiple serotonin (5-HT) and dopamine receptors and produces characteristic alterations in perception, mood and self-experience. However, human data linking specific receptor actions of LSD to large-scale functional brain network changes remain limited, and prior connectivity studies have been constrained by seed-based approaches and have not systematically addressed the influence of global signal (GS) artefacts. This study set out to characterise time-dependent, receptor-mediated effects of LSD on whole-brain functional connectivity using a data-driven Global Brain Connectivity (GBC) metric, and to relate those connectivity patterns to cortical gene expression maps for candidate receptors. Preller and colleagues hypothesised that LSD-induced GBC changes would spatially match cortical expression of the HTR2A gene (encoding the 5-HT2A receptor), that ketanserin (a 5-HT2A antagonist) would block LSD effects, and that artefact removal via global signal regression (GSR) would materially influence GBC findings. The work therefore aims both to specify the receptor basis of LSD-induced network changes and to evaluate methodological factors relevant to pharmacological resting-state fMRI.

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Study Details

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