Abstract
Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of vigilance. Here, we performed chronic electrophysiological recordings from the neocortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We report an acute induction of a dissociated state, characterised by prominent slow oscillations in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was initially markedly suppressed, but was overcompensated in the subsequent 48 hours, while administration of 5-MeO-DMT immediately after sleep deprivation attenuated the subsequent rebound of sleep slow-wave activity. We argue that the occurrence of a dissociated state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics — from dream-like hallucinations to reopening of the critical period for plasticity.
Similar content being viewed by others
Data availability
All data presented in this manuscript are available on figshare (10.6084/m9.figshare.30058069). All raw data are available upon reasonable request to the corresponding authors.
Code availability
All codes are available upon reasonable request to the corresponding authors.
References
Jouvet, M., Michel, F. & Courjon, J. On a stage of rapid cerebral electrical activity in the course of physiological sleep. C. R. Seances Soc. Biol. Fil. 153, 1024–1028 (1959).
Piéron, H. Le Problème Physiologique Du Sommeil. (Masson et Cie, 1913).
Campbell, S. S. & Tobler, I. Animal sleep: a review of sleep duration across phylogeny. Neurosci. Biobehav. Rev. 8, 269–300 (1984).
Blanco-Duque, C. et al. Oscillatory-Quality of sleep spindles links brain state with sleep regulation and function. Sci. Adv. 10, eadn6247 (2024).
Dement, W. The occurrence of low voltage, fast, electroencephalogram patterns during behavioral sleep in the cat. Electroencephalogr. Clin. Neurophysiol. 10, 291–296 (1958).
Vyazovskiy, V. V. et al. Local sleep in awake rats. Nature 472, 443–447 (2011).
Sarasso, S. et al. Local sleep-like cortical reactivity in the awake brain after focal injury. Brain 143, 3672–3684 (2020).
Walker, J. M., Glotzbach, S. F., Berger, R. J. & Heller, H. C. Sleep and hibernation in ground squirrels (Citellus spp): electrophysiological observations. Am. J. Physiol. 233, R213–R221 (1977).
Vyazovskiy, V. V., Palchykova, S., Achermann, P., Tobler, I. & Deboer, T. Different effects of sleep deprivation and torpor on EEG slow-wave characteristics in Djungarian hamsters. Cereb. Cortex 27, 950–961 (2017).
Miyasaka, M. & Domino, E. F. Neural mechanisms of ketamine-induced anesthesia. Int. J. Neuropharmacol. 7, 557–573 (1968).
Campbell, I. G. & Feinberg, I. NREM delta stimulation following MK-801 is a response of sleep systems. J. Neurophysiol. 76, 3714–3720 (1996).
Campbell, I. G. & Feinberg, I. Comparison of MK-801 and sleep deprivation effects on NREM, REM, and waking spectra in the rat. Sleep 22, 423–432 (1999).
Ammirati, F., Colivicchi, F., Di Battista, G., Garelli, F. F. & Santini, M. Electroencephalographic correlates of vasovagal syncope induced by head-up tilt testing. Stroke 29, 2347–2351 (1998).
Husain, A. M. Electroencephalographic assessment of coma. J. Clin. Neurophysiol. 23, 208–220 (2006).
Guillaumin, M. C. C. et al. Deficient synaptic neurotransmission results in a persistent sleep-like cortical activity across vigilance states in mice. Curr. Biol. 35, 1716–1729.e3 (2025).
Vanhatalo, S. & Kaila, K. Development of neonatal EEG activity: from phenomenology to physiology. Semin. Fetal Neonatal Med. 11, 471–478 (2006).
Hinard, V. et al. Key electrophysiological, molecular, and metabolic signatures of sleep and wakefulness revealed in primary cortical cultures. J. Neurosci. 32, 12506–12517 (2012).
Sanchez-Vives, M. V., Massimini, M. & Mattia, M. Shaping the default activity pattern of the cortical network. Neuron 94, 993–1001 (2017).
Yaden, D. B., Goldy, S. P., Weiss, B. & Griffiths, R. R. Clinically relevant acute subjective effects of psychedelics beyond mystical experience. Nat. Rev. Psychol. 3, 606–621 (2024).
Griffiths, R. R. et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J. Psychopharmacol. 30, 1181–1197 (2016).
Ross, S. et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30, 1165–1180 (2016).
Carhart-Harris, R. L. & Goodwin, G. M. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology 42, 2105–2113 (2017).
Rucker, J. J. H., Iliff, J. & Nutt, D. J. Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology 142, 200–218 (2018).
Nardou, R. et al. Psychedelics reopen the social reward learning critical period. Nature 618, 790–798 (2023).
Shao, L.-X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 109, 2535–2544.e4 (2021).
Vaidya, V. A., Marek, G. J., Aghajanian, G. K. & Duman, R. S. 5-HT(2A) receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785–2795 (1997).
Heifets, B. D. & Olson, D. E. Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology 49, 104–118 (2024).
Bréant, B. J. B. et al. Psychedelic compound 5-MeO-DMT induces an altered wake state in mice. Sleep. Med. 100, S22 (2022).
Souza, A. C. et al. 5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats. Sci. Rep. 14, 11281 (2024).
Karalis, N. et al. 4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior. Nat. Neurosci. 19, 605–612 (2016).
Bagur, S. et al. Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation. Nat. Commun. 12, 1–15 (2021).
Vyazovskiy, V. V., Cirelli, C. & Tononi, G. Electrophysiological correlates of sleep homeostasis in freely behaving rats. Prog. Brain Res. 193, 17–38 (2011).
Palagini, L., Baglioni, C., Ciapparelli, A., Gemignani, A. & Riemann, D. REM sleep dysregulation in depression: state of the art. Sleep. Med. Rev. 17, 377–390 (2013).
He, B. J., Zempel, J. M., Snyder, A. Z. & Raichle, M. E. The temporal structures and functional significance of scale-free brain activity. Neuron 66, 353–369 (2010).
Lendner, J. D. et al. An electrophysiological marker of arousal level in humans. Elife 9, (2020).
Neske, G. T. The slow oscillation in cortical and thalamic networks: mechanisms and functions. Front. Neural Circuits 9, (2016).
Kahn, M. et al. Neuronal-spiking-based closed-loop stimulation during cortical ON- and OFF-states in freely moving mice. J. Sleep Res. 31, (2022).
Harding, C. D. et al. Detection of neuronal OFF periods as low amplitude neural activity segments. BMC Neurosci. 24, 13 (2023).
Vyazovskiy, V. V. et al. Cortical firing and sleep homeostasis. Neuron 63, 865–878 (2009).
Borbély, A. A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982).
Borbély, A. A., Daan, S., Wirz-Justice, A. & Deboer, T. The two-process model of sleep regulation: a reappraisal. J. Sleep. Res. 25, 131–143 (2016).
Andrillon, T., Burns, A., Mackay, T., Windt, J. & Tsuchiya, N. Predicting lapses of attention with sleep-like slow waves. Nat. Commun. 12, 1–12 (2021).
Stephan, A. M., Lecci, S., Cataldi, J. & Siclari, F. Conscious experiences and high-density EEG patterns predicting subjective sleep depth. Curr. Biol. 31, 5487–5500.e3 (2021).
Ungurean, G., Martinez-Gonzalez, D., Massot, B., Libourel, P.-A. & Rattenborg, N. C. Pupillary behavior during wakefulness, non-REM sleep, and REM sleep in birds is opposite that of mammals. Curr. Biol. 31, 5370–5376.e4 (2021).
Yüzgeç, Ö, Prsa, M., Zimmermann, R. & Huber, D. Pupil size coupling to cortical states protects the stability of deep sleep via parasympathetic modulation. Curr. Biol. 28, 392–400.e3 (2018).
Carro-Domínguez, M. et al. Pupil size reveals arousal level fluctuations in human sleep. Nat. Commun. 16, 2070 (2025).
Ungurean, G. & Rattenborg, N. C. A mammal and bird’s-eye-view of the pupil during sleep and wakefulness. Eur. J. Neurosci. 59, 584–594 (2024).
Buzsáki, G., Haubenreiser, J., Grastyán, E., Czopf, J. & Kellényi, L. Hippocampal slow wave activity during appetitive and aversive conditioning in the cat. Electroencephalogr. Clin. Neurophysiol. 51, 276–290 (1981).
Vanderwolf, C. H. The electrocorticogram in relation to physiology and behavior: a new analysis. Electroencephalogr. Clin. Neurophysiol. 82, 165–175 (1992).
Willins, D. L. & Meltzer, H. Y. Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J. Pharmacol. Exp. Ther. 282, 699 (1997).
Shen, H.-W., Jiang, X.-L., Winter, J. C. & Yu, A.-M. Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Curr. Drug Metab. 11, 659 (2010).
Ermakova, A. O., Dunbar, F., Rucker, J. & Johnson, M. W. A narrative synthesis of research with 5-MeO-DMT. J. Psychopharmacol. 36, 273–294 (2022).
Blackburne, G. et al. Complex slow waves in the human brain under 5-MeO-DMT. Cell Rep. 44, 116040 (2025).
Koch, C. The void and the brain. Cell Rep. 44, 116072 (2025).
Shen, H.-W., Jiang, X.-L. & Yu, A.-M. Development of a LC-MS/MS method to analyze 5-methoxy-N,N-dimethyltryptamine and bufotenine, and application to pharmacokinetic study. Bioanalysis 1, 87–95 (2009).
Jefferson, S. J. et al. 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice. bioRxiv 11, 515044 (2022).
Riga, M. S., Lladó-Pelfort, L., Artigas, F. & Celada, P. The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT 1A and 5-HT 2A receptors. Neuropharmacology 142, 219–230 (2018).
Thomas, C. W., Guillaumin, M. C., McKillop, L. E., Achermann, P. & Vyazovskiy, V. V. Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity. Elife 9, (2020).
El-Kanbi, K., de Lavilléon, G., Bagur, S., Lacroix, M. & Benchenane, K. Distinction between slow waves and delta waves sheds light to sleep homeostasis and their association to hippocampal sharp waves ripples. bioRxiv 12, 522034 (2022).
González-Maeso, J. et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53, 439–452 (2007).
Hanks, J. B. & González-Maeso, J. Animal models of serotonergic psychedelics. ACS Chem. Neurosci. 4, 33–42 (2013).
Fox, M. A., Stein, A. R., French, H. T. & Murphy, D. L. Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT): 5-HT1A/5-HT2A interactions in SERT-deficient mice. Br. J. Pharmacol. 159, 879–887 (2010).
Krone, L. B. et al. A role for the cortex in sleep-wake regulation. Nat. Neurosci. 24, 1210–1215 (2021).
Shao, L.-X. et al. Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors. Nature 642, 411–420 (2025).
Javoy-Agid, F. et al. Distribution of monoaminergic, cholinergic, and GABAergic markers in the human cerebral cortex. Neuroscience 29, 251–259 (1989).
Sakai, K. Sleep-waking discharge profiles of dorsal raphe nucleus neurons in mice. Neuroscience 197, 200–224 (2011).
Trulson, M. E. & Jacobs, B. L. Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res 163, 135–150 (1979).
Trulson, M. E. & Trulson, V. M. Activity of nucleus raphe pallidus neurons across the sleep-waking cycle in freely moving cats. Brain Res 237, 232–237 (1982).
Jouvet, M. Sleep and serotonin an unfinished story. Neuropsychopharmacology 21, 24S–27S (1999).
Portas, C. M., Thakkar, M., Rainnie, D. & McCarley, R. W. Microdialysis perfusion of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal raphe nucleus decreases serotonin release and increases rapid eye movement sleep in the freely moving cat. J. Neurosci. Official J. Soc. Neurosci. 16, (1996).
Monti, J. M. Serotonin control of sleep-wake behavior. Sleep. Med. Rev. 15, 269–281 (2011).
Vyazovskiy, V. V. & Tobler, I. The temporal structure of behaviour and sleep homeostasis. PLoS One 7, (2012).
Vanderwolf, C. H. & Robinson, T. E. Reticulo-cortical activity and behavior: A critique of the arousal theory and a new synthesis. Behav. Brain Sci. 4, 459–514 (1981).
Davis, C. J., Clinton, J. M., Jewett, K. A., Zielinski, M. R. & Krueger, J. M. Delta wave power: an independent sleep phenotype or epiphenomenon?. J. Clin. Sleep. Med. 7, S16 (2011).
Meyer, A. F., Poort, J., O’Keefe, J., Sahani, M. & Linden, J. F. A head-mounted camera system integrates detailed behavioral monitoring with multichannel electrophysiology in freely moving mice. Neuron 100, 46–60.e7 (2018).
Bremer, F. Activité Electrique Du Cortex Cerebral Dans Les Etats De Sommeil Et De Veille Chez Le Chat. Comptes rendus des. seances de. la Soc. de. biologie et. de. ses. filiales 88, 465–467 (1936).
Magoun, H. W. Caudal and cephalic influences of the brain stem reticular formation. Physiol. Rev. 30, 459–474 (1950).
Jouvet, M. & Michel, F. Study of the cerebral electrical activity during sleep. C. R. Seances Soc. Biol. Fil. 152, 1167–1170 (1958).
Jouvet, M. & Michel, F. Electromyographic correlations of sleep in the chronic decorticate & mesencephalic cat. C. R. Seances Soc. Biol. Fil. 153, 422–425 (1959).
Barrett, F. S., Johnson, M. W. & Griffiths, R. R. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J. Psychopharmacol. 29, 1182 (2015).
Barsuglia, J. et al. Intensity of mystical experiences occasioned by 5-MeO-DMT and comparison with a prior psilocybin study. Front. Psychol. 9, (2018).
Goodwin, G. M. et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology 48, (2023).
Zarate, C. A. et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol. Psychiatry 71, 939–946 (2012).
Blumberg, M. S., Dooley, J. C. & Tiriac, A. Sleep, plasticity, and sensory neurodevelopment. Neuron 110, 3230–3242 (2022).
Lee, E. E., Della Selva, M. P., Liu, A. & Himelhoch, S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen. Hosp. Psychiatry 37, 178–184 (2015).
Zanos, P. et al. Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacol. Rev. 70, 621–660 (2018).
Cichon, J. et al. Ketamine triggers a switch in excitatory neuronal activity across neocortex. Nat. Neurosci. 26, 39–52 (2023).
Duncan, W. C. et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 16, 301–311 (2013).
Duncan, W. C. Jr, Ballard, E. D. & Zarate, C. A. Ketamine-induced glutamatergic mechanisms of sleep and wakefulness: Insights for developing novel treatments for disturbed sleep and mood. Handb. Exp. Pharmacol. 253, 337–358 (2019).
Wikler, A. Pharmacologic dissociation of behavior and EEG “sleep patterns” in dogs; morphine, n-allylnormorphine, and atropine. Proc. Soc. Exp. Biol. Med. 79, 261–265 (1952).
Castro-Zaballa, S. et al. EEG dissociation induced by muscarinic receptor antagonists: Coherent 40 Hz oscillations in a background of slow waves and spindles. Behav. Brain Res. 359, 28–37 (2019).
Frohlich, J., Mediano, P. A. M., Bavato, F. & Gharabaghi, A. Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness. Commun. Biol. 6, 654 (2023).
de Vivo, L. et al. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science 355, 507–510 (2017).
Bartram, J. et al. Cortical Up states induce the selective weakening of subthreshold synaptic inputs. Nat. Commun. 8, 665 (2017).
Tononi, G. & Cirelli, C. Sleep function and synaptic homeostasis. Sleep. Med. Rev. 10, 49–62 (2006).
Siegel, J. S. et al. Psilocybin desynchronizes the human brain. Nature 632, 131–138 (2024).
Šabanović, M. et al. Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility. Mol. Psychiatry 1, 14 (2024).
O’Keefe, J. Hippocampus, theta, and spatial memory. Curr. Opin. Neurobiol. 3, 917–924 (1993).
O’Keefe, J. & Recce, M. L. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3, 317–330 (1993).
Chemel, B. R., Roth, B. L., Armbruster, B., Watts, V. J. & Nichols, D. E. WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology 188, 244–251 (2006).
Barbanoj, M. J. et al. Daytime Ayahuasca administration modulates REM and slow-wave sleep in healthy volunteers. Psychopharmacology 196, 315–326 (2008).
Dudysová, D. et al. The effects of daytime psilocybin administration on sleep: implications for antidepressant action. Front. Pharmacol. 11, 602590 (2020).
Thomas, C. W. et al. Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice. Transl. Psychiatry 12, 77 (2022).
Deliens, G., Gilson, M. & Peigneux, P. Sleep and the processing of emotions. Exp. Brain Res. 232, 1403–1414 (2014).
Du, Y. et al. Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Chin. Med. J. 136, 2983–2992 (2023).
Castrén, E. Is mood chemistry?. Nat. Rev. Neurosci. 6, 241–246 (2005).
Fisher, S. P. et al. Stereotypic wheel running decreases cortical activity in mice. Nat. Commun. 7, (2016).
Milinski, L. et al. Waking experience modulates sleep need in mice. BMC Biol. 19, 65 (2021).
Huber, R., Tononi, G. & Cirelli, C. Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep 30, 129–139 (2007).
McKillop, L. E. et al. Effects of aging on cortical neural dynamics and local sleep homeostasis in mice. J. Neurosci. 38, 3911 (2018).
Scheffer-Teixeira, R. & Tort, A. B. L. Theta-gamma cross-frequency analyses (hippocampus). Encycl. Comput. Neurosci. 1, 15 (2018).
Acknowledgements
The authors would like to thank Laura McKillop, Christian Harding, Elise Meijer and Sian Wilcox for their assistance with surgery, drug preparation, equipment setup, animal husbandry, or data analysis; Gianina Ungurean and Niels Rattenborg for advice on ordering and installation of miniature cameras for monitoring pupil diameter; Stuart Peirson and Carina Pothecary on the materials and review of the oculometer; Vanda Reiss for her drawing of a mouse wearing the occulometer (Fig. 4.a); Matt Jones for his valuable comments; and Beckley Psytech for providing the compound for this study. The study was funded by UK Biotechnology and Biological Sciences Research Council grant (BB/M011224/1); Wellcome Trust Senior Investigator Award (106174/Z/14/Z); Wellcome Trust Strategic Award (098461/Z/12/Z); John Fell OUP Research Fund Grant (131/032); and the Medical Research Council (MR/S01134X/1).
Author information
Authors and Affiliations
Contributions
B.J.B.B.: Conceptualisation; Methodology, Investigation, Visualisation, Funding acquisition, Writing (original draft, review and editing). J.P.M.: Methodology, Visualisation, Writing (review and editing). A.A.: Methodology, Visualisation, Writing (review and editing). A.H.S.: Methodology, Visualisation, Writing (review and editing). J.P.: Methodology, Visualisation, Writing (review and editing). D.M.B.: Conceptualisation, Supervision, Writing (review and editing). T.S.: Conceptualisation, Supervision, Writing (review and editing). V.V.V.: Conceptualisation, Investigation, Funding acquisition, Supervision, Writing (original draft, review and editing)
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Communications Biology thanks Francesca Siclari, Yuer Wu and the other anonymous reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Joao Valente.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Bréant, B.J.B., Prius Mengual, J., Andrews, A. et al. Vigilance state dissociation induced by 5-MeO-DMT in mice. Commun Biol (2026). https://doi.org/10.1038/s42003-025-09412-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-025-09412-x
