Classical and non-classical psychedelic drugs induce common network changes in human cortex

This fMRI analysis study (n=74 total) looks at how three different drugs – nitrous oxide, ketamine, and lysergic acid diethylamide (LSD) – affect the way different parts of the brain communicate with each other. By comparing brain scans taken before and during drug use, the study found that all three drugs reduced connectivity within certain networks in the brain, while enhancing connections between different networks. These effects were seen in areas of the brain that are important for our conscious experiences. The study suggests that both classical and non-classical psychedelics affect the brain similarly and identifies a region of the brain that may be responsible for the drugs’ effects.


The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical “hot zone,” posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.

Authors: Rui Dai, Tony E. Larkin, Zirui Huang, Vijay Tarnal, Paul Picton, Phillip E. Vlisides, Ellen Janke, Amy McKinney, Anthony G. Hudetz, Richard E. Harris & George A. Mashour

Summary of Classical and non-classical psychedelic drugs induce common network changes in human cortex

The neurobiological basis of the psychedelic experience remains incompletely understood. Still, non-classical psychedelics induce similar phenomenology, increase neurophysiologic complexity, depress posterior cortical alpha oscillations, expand the repertoire of functional brain connectivity states, and induce neuroplasticity.

Nitrous oxide has been another NMDA receptor antagonist in continuous clinical use as an anaesthetic since the mid-19th century. Although some studies show spectral, functional connectivity, and complexity changes associated with nitrous oxide, no studies show changes in functional brain networks associated with psychedelic effects.

The authors conducted a neuroimaging study of healthy human volunteers before and after exposure to psychedelic nitrous oxide concentrations. They compared the neural correlates of the psychedelic experience induced by nitrous oxide to other drugs, including ketamine and LSD.

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Classical and non-classical psychedelic drugs induce common network changes in human cortex

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Cite this paper (APA)

Dai, R., Larkin, T. E., Huang, Z., Tarnal, V., Picton, P., Vlisides, P. E., ... & Mashour, G. A. (2023). Classical and Non-Classical Psychedelic Drugs Induce Common Network Changes in Human Cortex. NeuroImage, 120097.

Study details

Compounds studied
LSD Nitrous Oxide Ketamine

Topics studied

Study characteristics
Open-Label Re-analysis Bio/Neuro

74 Humans

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