K. Preller, Adeel Razi, P. Zeidman
Jan 28, 2019
Citations
4
Influential Citations
168
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Quality indicators
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
Significance Lysergic acid diethylamide (LSD) is a psychedelic drug that reliably induces an altered state of consciousness. Interest in psychedelic compounds is growing due to their remarkable potential for understanding altered neural states and potential clinical applications. However, there are major knowledge gaps regarding LSD’s neuropharmacology. Using cutting-edge neuroimaging methods we investigated directed connectivity between cortico–striato–thalamo-cortical (CSTC) regions after administration of LSD together with the specific role of the serotonin 2A receptor. Our results provide evidence that LSD alters directed connectivity within CSTC pathways in humans, suggesting that a disintegration of information processing within these loops is underlying the psychedelic state. These results inform the neurobiology of altered states of consciousness with critical implications for rational development of novel treatments. Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico–striato–thalamo-cortical (CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.