Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The neural basis of psychedelic action

Abstract

Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin receptors and their downstream molecular signaling pathways, emphasizing key elements for drug discovery. We consider the impact of psychedelics on neuronal spiking dynamics in several cortical and subcortical regions, along with transcriptional changes and sustained effects on structural plasticity. Finally, we summarize neuroimaging results that pinpoint effects on association cortices and thalamocortical functional connectivity, which inform current theories of psychedelic action. By synthesizing knowledge across the chemical, molecular, neuronal, and network levels, we hope to provide an integrative perspective on the neural mechanisms responsible for the acute and enduring effects of psychedelics on behavior.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Chemical phylogeny of psychedelics.
Fig. 2: The 5-HT2A receptors and molecular signaling pathways.
Fig. 3: Regional differences in psychedelic action on neurophysiology.
Fig. 4: Network-level models of psychedelic action.

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Nichols, D. E. & Walter, H. The history of psychedelics in psychiatry. Pharmacopsychiatry 54, 151–166 (2021).

    Article  PubMed  Google Scholar 

  2. Davis, A. K. et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry 78, 481–489 (2021).

    Article  PubMed  Google Scholar 

  3. Carhart-Harris, R. et al. Trial of psilocybin versus escitalopram for depression. N. Engl. J. Med. 384, 1402–1411 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Johnson, M. W., Garcia-Romeu, A. & Griffiths, R. R. Long-term follow-up of psilocybin-facilitated smoking cessation. Am. J. Drug Alcohol Abuse 43, 55–60 (2017).

    Article  PubMed  Google Scholar 

  5. Nichols, D. E. Psychedelics. Pharm. Rev. 68, 264–355 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vollenweider, F. X. & Preller, K. H. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat. Rev. Neurosci. 21, 611–624 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Kelmendi, B., Kaye, A. P., Pittenger, C. & Kwan, A. C. Psychedelics. Curr. Biol. 32, R63–R67 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. McClure-Begley, T. D. & Roth, B. L. The promises and perils of psychedelic pharmacology for psychiatry. Nat. Rev. Drug Discov. 21, 463–473 (2022).

  9. Kim, K. et al. Structure of a hallucinogen-activated Gq-coupled 5-HT2A serotonin receptor. Cell 182, 1574–1588 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cao, D. et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science 375, 403–411 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Froldi, G., Silvestrin, B., Dorigo, P. & Caparrotta, L. Gramine: a vasorelaxing alkaloid acting on 5-HT2A receptors. Planta Med. 70, 373–375 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Dong, C. et al. Psychedelic-inspired drug discovery using an engineered biosensor. Cell 184, 2779–2792 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Glennon, R. A., Liebowitz, S. M. & Mack, E. C. Serotonin receptor-binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogs. J. Med. Chem. 21, 822–825 (1978).

    Article  CAS  PubMed  Google Scholar 

  14. Lyon, R. A., Titeler, M., Seggel, M. R. & Glennon, R. A. Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens. Eur. J. Pharmacol. 145, 291–297 (1988).

    Article  CAS  PubMed  Google Scholar 

  15. McLean, T. H. et al. 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. J. Med. Chem. 49, 5794–5803 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Halberstadt, A. L., Chatha, M., Stratford, A., Grill, M. & Brandt, S. D. Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (‘FLY’) and benzodifuran (‘DragonFLY’) analogs. Neuropharmacology 144, 368–376 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Mantle, T. J., Tipton, K. F. & Garrett, N. J. Inhibition of monoamine oxidase by amphetamine and related compounds. Biochem. Pharmacol. 25, 2073–2077 (1976).

    Article  CAS  PubMed  Google Scholar 

  18. Glennon, R. A., Young, R. & Jacyno, J. M. Indolealkylamine and phenalkylamine hallucinogens—effect of α-methyl and N-methyl substituents on behavioral activity. Biochem. Pharmacol. 32, 1267–1273 (1983).

    Article  CAS  PubMed  Google Scholar 

  19. Dyer, D. C., Nichols, D. E., Rusterholz, D. B. & Barfknecht, C. F. Comparative effects of stereoisomers of psychotomimetic phenylisopropylamines. Life Sci. 13, 885–896 (1973).

    Article  CAS  PubMed  Google Scholar 

  20. Congreve, M., Carr, R., Murray, C. & Jhoti, H. A ‘rule of three’ for fragment-based lead discovery? Drug Discov. Today 8, 876–877 (2003).

    Article  PubMed  Google Scholar 

  21. Wager, T. T., Hou, X., Verhoest, P. R. & Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 1, 435–449 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Takahashi, T. et al. 11C labeling of indolealkylamine alkaloids and the comparative-study of their tissue distributions. Int. J. Appl. Radiat. Isot. 36, 965–969 (1985).

    Article  CAS  PubMed  Google Scholar 

  23. Ebersole, B. J., Visiers, I., Weinstein, H. & Sealfon, S. C. Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy. Mol. Pharmacol. 63, 36–43 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Banskota, S., Ghia, J. E. & Khan, W. I. Serotonin in the gut: blessing or a curse. Biochimie 161, 56–64 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Barfknecht, C. F. & Nichols, D. E. Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients. J. Med. Chem. 18, 208–210 (1975).

    Article  CAS  PubMed  Google Scholar 

  26. Perrin, D. D. Dissociation Constants of Organic Bases in Aqueous Solution (Butterworths, 1965).

  27. Migliaccio, G. P., Shieh, T. L. N., Byrn, S. R., Hathaway, B. A. & Nichols, D. E. Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR-spectroscopy. J. Med. Chem. 24, 206–209 (1981).

    Article  CAS  PubMed  Google Scholar 

  28. Adams, A. M. et al. In vivo production of psilocybin in E. coli. Metab. Eng. 56, 111–119 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Milne, N. et al. Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives. Metab. Eng. 60, 25–36 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Babler, A., Vogel, H. & Hell, D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9, 3897–3902 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Preller, K. H. et al. The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Curr. Biol. 27, 451–457 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Madsen, M. K. et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology 44, 1328–1334 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Glennon, R. A., Titeler, M. & McKenney, J. D. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 35, 2505–2511 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach, J. & Brandt, S. D. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology 167, 107933 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Keiser, M. J. et al. Predicting new molecular targets for known drugs. Nature 462, 175–181 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gonzalez-Maeso, J. et al. Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53, 439–452 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marona-Lewicka, D., Thisted, R. A. & Nichols, D. E. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology 180, 427–435 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Grailhe, R. et al. Increased exploratory activity and altered response to LSD in mice lacking the 5-HT5A receptor. Neuron 22, 581–591 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Marona-Lewicka, D., Chemel, B. R. & Nichols, D. E. Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI. Psychopharmacology 203, 265–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Klein, A. K. et al. Investigation of the structure–activity relationships of psilocybin analogues. ACS Pharm. Transl. Sci. 4, 533–542 (2021).

    Article  CAS  Google Scholar 

  42. Pokorny, T., Preller, K. H., Kraehenmann, R. & Vollenweider, F. X. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience. Eur. Neuropsychopharmacol. 26, 756–766 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B. & Thompson, S. M. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc. Natl Acad. Sci. USA 118, e2022489118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shao, L. X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 109, 2535–2544 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sard, H. et al. SAR of psilocybin analogs: discovery of a selective 5-HT2C agonist. Bioorg. Med. Chem. Lett. 15, 4555–4559 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Wacker, D. et al. Structural features for functional selectivity at serotonin receptors. Science 340, 615–619 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wacker, D. et al. Crystal structure of an LSD-bound human serotonin receptor. Cell 168, 377–389 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Roth, B. L. Drugs and valvular heart disease. N. Engl. J. Med. 356, 6–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Droogmans, S. et al. Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease. Am. J. Cardiol. 100, 1442–1445 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Setola, V. et al. 3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol. 63, 1223–1229 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Roth, B. L., Nakaki, T., Chuang, D. M. & Costa, E. Aortic recognition sites for serotonin (5HT) are coupled to phospholipase C and modulate phosphatidylinositol turnover. Neuropharmacology 23, 1223–1225 (1984).

    Article  CAS  PubMed  Google Scholar 

  52. Roth, B. L., Nakaki, T., Chuang, D. M. & Costa, E. 5-Hydroxytryptamine 2 receptors coupled to phospholipase C in rat aorta: modulation of phosphoinositide turnover by phorbol ester. J. Pharmacol. Exp. Ther. 238, 480–485 (1986).

    CAS  PubMed  Google Scholar 

  53. Kristiansen, K. et al. A highly conserved aspartic acid (Asp-155) anchors the terminal amine moiety of tryptamines and is involved in membrane targeting of the 5-HT2A serotonin receptor but does not participate in activation via a ‘salt-bridge disruption’ mechanism. J. Pharmacol. Exp. Ther. 293, 735–746 (2000).

    CAS  PubMed  Google Scholar 

  54. Egan, C. et al. Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors. Synapse 35, 144–150 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Gray, J. A., Bhatnagar, A., Gurevich, V. V. & Roth, B. L. The interaction of a constitutively active arrestin with the arrestin-insensitive 5-HT2A receptor induces agonist-independent internalization. Mol. Pharmacol. 63, 961–972 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Felder, C. C., Kanterman, R. Y., Ma, A. L. & Axelrod, J. Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc. Natl Acad. Sci. USA 87, 2187–2191 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Garcia, E. E., Smith, R. L. & Sanders-Bush, E. Role of Gq protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology 52, 1671–1677 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schmid, C. L., Raehal, K. M. & Bohn, L. M. Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo. Proc. Natl Acad. Sci. USA 105, 1079–1084 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rodriguiz, R. M. et al. LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1. Sci. Rep. 11, 17690 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kurrasch-Orbaugh, D. M., Parrish, J. C., Watts, V. J. & Nichols, D. E. A complex signaling cascade links the serotonin 2A receptor to phospholipase A2 activation: the involvement of MAP kinases. J. Neurochem. 86, 980–991 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Zhuang, Y. et al. Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell 184, 931–942 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hasler, F., Bourquin, D., Brenneisen, R., Bar, T. & Vollenweider, F. X. Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharm. Acta Helv. 72, 175–184 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Brandt, S. D. et al. Return of the lysergamides. Part I: analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD). Drug Test. Anal. 8, 891–902 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Vargas, M. V., Meyer, R., Avanes, A. A., Rus, M. & Olson, D. E. Psychedelics and other psychoplastogens for treating mental illness. Front. Psychiatry 12, 727117 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Olson, D. E. Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J. Exp. Neurosci. 12, 1179069518800508 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Dunlap, L. E. et al. Identification of psychoplastogenic N,N-dimethylaminoisotryptamine (isoDMT) analogues through structure–activity relationship studies. J. Med. Chem. 63, 1142–1155 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cameron, L. P. et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 589, 474–479 (2020).

  68. Lyu, J. et al. Ultra-large library docking for discovering new chemotypes. Nature 566, 224–229 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sadybekov, A. A. et al. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Nature 601, 452–459 (2022).

    Article  CAS  PubMed  Google Scholar 

  70. Araneda, R. & Andrade, R. 5-Hydroxytryptamine 2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40, 199–412 (1991).

    Article  Google Scholar 

  71. Davies, M. F., Deisz, R. A., Prince, D. A. & Peroutka, S. J. Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res. 423, 347–352 (1987).

    Article  CAS  PubMed  Google Scholar 

  72. Savalia, N. K., Shao, L. X. & Kwan, A. C. A dendrite-focused framework for understanding the actions of ketamine and psychedelics. Trends Neurosci. 44, 260–275 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Miner, L. A. H., Backstrom, J. R., Sanders-Bush, E. & Sesack, S. R. Ultrastructural localization of serotonin 2a receptors in the middle layers of the rat prelimibic prefrontal cortex. Neuroscience 116, 107–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Jakab, R. L. & Goldman-Rakic, P. S. 5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc. Natl Acad. Sci. USA 95, 735–740 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Willins, D. L., Deutch, A. Y. & Roth, B. L. Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27, 79–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Aghajanian, G. K. & Marek, G. J. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36, 589–599 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Santana, N., Bortolozzi, A., Serrats, J., Mengod, G. & Artigas, F. Expression of serotonin 1A and serotonin 2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb. Cortex 14, 1100–1109 (2004).

    Article  PubMed  Google Scholar 

  78. Martin, D. A. & Nichols, C. D. Psychedelics recruit multiple cellular types and produce complex transcriptional responses within the brain. EBioMedicine 11, 262–277 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Avesar, D. & Gulledge, A. T. Selective serotonergic excitation of callosal projection neurons. Front. Neural Circuits 6, 12 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wood, J., Kim, Y. & Moghaddam, B. Disruption of prefrontal cortex large scale neuronal activity by different classes of psychotomimetic drugs. J. Neurosci. 32, 3022–3031 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Evarts, E. V., Landau, W., Freygang, W. Jr. & Marshall, W. H. Some effects of lysergic acid diethylamide and bufotenine. Am. J. Physiol. 182, 594–598 (1955).

    Article  CAS  PubMed  Google Scholar 

  82. Rose, D. & Horn, G. Effects of LSD on the responses of single units in cat visual cortex. Exp. Brain Res. 27, 71–80 (1977).

    Article  CAS  PubMed  Google Scholar 

  83. Michaiel, A. M., Parker, P. R. L. & Niell, C. M. A hallucinogenic serotonin-2A receptor agonist reduces visual response gain and alters temporal dynamics in mouse V1. Cell Rep. 26, 3475–3483 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Aghajanian, G. K., Foote, W. E. & Sheard, M. H. Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science 161, 706–708 (1968).

    Article  CAS  PubMed  Google Scholar 

  85. Aghajanian, G. K., Foote, W. E. & Sheard, M. H. Action of psychotogenic drugs on single midbrain raphe neurons. J. Pharmacol. Exp. Ther. 171, 178–187 (1970).

    CAS  PubMed  Google Scholar 

  86. Sprouse, J. S. & Aghajanian, G. K. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse 1, 3–9 (1987).

    Article  CAS  PubMed  Google Scholar 

  87. Trulson, M. E., Ross, C. A. & Jacobs, B. L. Lack of tolerance to the depression of raphe unit activity by lysergic acid diethylamide. Neuropharmacology 16, 771–774 (1977).

    Article  CAS  PubMed  Google Scholar 

  88. Trulson, M. E. & Jacobs, B. L. Dissociations between the effects of LSD on behavior and raphe unit-activity in freely moving cats. Science 205, 515–518 (1979).

    Article  CAS  PubMed  Google Scholar 

  89. Domenico, C., Haggerty, D., Mou, X. & Ji, D. LSD degrades hippocampal spatial representations and suppresses hippocampal–visual cortical interactions. Cell Rep. 36, 109714 (2021).

    Article  CAS  PubMed  Google Scholar 

  90. Rasmussen, K. & Aghajanian, G. K. Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists. Brain Res. 385, 395–400 (1986).

    Article  CAS  PubMed  Google Scholar 

  91. Aghajanian, G. K. LSD and CNS transmission. Annu. Rev. Pharm. 12, 157–168 (1972).

    Article  CAS  Google Scholar 

  92. Nichols, C. D. & Sanders-Bush, E. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology 26, 634–642 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Vaidya, V. A., Marek, G. J., Aghajanian, G. K. & Duman, R. S. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785–2795 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. de la Fuente Revenga, M. et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 37, 109836 (2021).

    Article  PubMed  Google Scholar 

  95. Jones, K. A. et al. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc. Natl Acad. Sci. USA 106, 19575–19580 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yoshida, H. et al. Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro. Neurosci. Res. 71, 311–314 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Ly, C. et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 23, 3170–3182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Raval, N. R. et al. A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int. J. Mol. Sci. 22, 835 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  99. Ly, C. et al. Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacol. Transl. Sci. 4, 452–460 (2020).

  100. Phoumthipphavong, V., Barthas, F., Hassett, S. & Kwan, A. C. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro 3, ENEURO.0133-0115.2016 (2016).

  101. Ali, F. et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat. Commun. 11, 72 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Aleksandrova, L. R. & Phillips, A. G. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol. Sci. 42, 929–942 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Hibicke, M., Landry, A. N., Kramer, H. M., Talman, Z. K. & Nichols, C. D. Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. ACS Chem. Neurosci. 11, 864–871 (2020).

    Article  CAS  PubMed  Google Scholar 

  104. Hermle, L. et al. Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol. Psychiatry 32, 976–991 (1992).

    Article  CAS  PubMed  Google Scholar 

  105. Vollenweider, F. X. et al. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16, 357–372 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Carhart-Harris, R. L. et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc. Natl Acad. Sci. USA 109, 2138–2143 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lewis, C. R. et al. Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow. NeuroImage 159, 70–78 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Preller, K. H. et al. Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. eLife 7, e35082 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Muller, F., Dolder, P. C., Schmidt, A., Liechti, M. E. & Borgwardt, S. Altered network hub connectivity after acute LSD administration. NeuroImage Clin. 18, 694–701 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Madsen, M. K. et al. Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience. Eur. Neuropsychopharmacol. 50, 121–132 (2021).

    Article  CAS  PubMed  Google Scholar 

  111. Preller, K. H. et al. Psilocybin induces time-dependent changes in global functional connectivity. Biol. Psychiatry 88, 197–207 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Muller, F. et al. Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Preller, K. H. et al. Effective connectivity changes in LSD-induced altered states of consciousness in humans. Proc. Natl Acad. Sci. USA 116, 2743–2748 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Beliveau, V. et al. A high-resolution in vivo atlas of the human brain’s serotonin system. J. Neurosci. 37, 120–128 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Deco, G. et al. Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD. Curr. Biol. 28, 3065–3074 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Burt, J. B. et al. Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD. eLife 10, e69320 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kringelbach, M. L. et al. Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proc. Natl Acad. Sci. USA 117, 9566–9576 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. McCulloch, D. E. et al. Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals. J. Psychopharmacol. 36, 74–84 (2022).

    Article  CAS  PubMed  Google Scholar 

  120. Barrett, F. S., Doss, M. K., Sepeda, N. D., Pekar, J. J. & Griffiths, R. R. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci. Rep. 10, 2214 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Doss, M. K. et al. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Transl. Psychiatry 11, 574 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Daws, R. E. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat. Med. 28, 844–851 (2022).

    Article  CAS  PubMed  Google Scholar 

  123. Stenbaek, D. S. et al. Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. J. Psychopharmacol. 35, 459–468 (2021).

    Article  CAS  PubMed  Google Scholar 

  124. Vollenweider, F. X. & Geyer, M. A. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res. Bull. 56, 495–507 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Carhart-Harris, R. L. & Friston, K. J. REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharm. Rev. 71, 316–344 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Corlett, P. R. et al. Hallucinations and strong priors. Trends Cogn. Sci. 23, 114–127 (2019).

    Article  PubMed  Google Scholar 

  127. Doss, M. K. et al. Models of psychedelic drug action: modulation of cortical–subcortical circuits. Brain 145, 441–456 (2021).

  128. Vollenweider, F. X., Csomor, P. A., Knappe, B., Geyer, M. A. & Quednow, B. B. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology 32, 1876–1887 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Schmid, Y. et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol. Psychiatry 78, 544–553 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Roseman, L. et al. LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion. Hum. Brain Mapp. 37, 3031–3040 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Schartner, M. M., Carhart-Harris, R. L., Barrett, A. B., Seth, A. K. & Muthukumaraswamy, S. D. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Sci. Rep. 7, 46421 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Timmermann, C. et al. Neural correlates of the DMT experience assessed with multivariate EEG. Sci. Rep. 9, 16324 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Alamia, A., Timmermann, C., Nutt, D. J., VanRullen, R. & Carhart-Harris, R. L. DMT alters cortical travelling waves. eLife 9, e59784 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Vernon, J., Marton, T. & Peterson, E. Sensory deprivation and hallucinations. Science 133, 1808–1812 (1961).

    Article  CAS  PubMed  Google Scholar 

  135. Powers, A. R., Mathys, C. & Corlett, P. R. Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science 357, 596–600 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Barrett, F. S., Krimmel, S. R., Griffiths, R. R., Seminowicz, D. A. & Mathur, B. N. Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention. NeuroImage 218, 116980 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Smith, R. L., Barrett, R. J. & Sanders-Bush, E. Neurochemical and behavioral evidence that quipazine–ketanserin discrimination is mediated by serotonin 2A receptor. J. Pharmacol. Exp. Ther. 275, 1050–1057 (1995).

    CAS  PubMed  Google Scholar 

  138. Palacios, J. M., Pazos, A. & Hoyer, D. A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment. Psychopharmacology 234, 1395–1418 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. Fitzgerald, L. W. et al. Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 21, 82S–90S (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Casey, A. B., Cui, M., Booth, R. G. & Canal, C. E. ‘Selective’ serotonin 5-HT2A receptor antagonists. Biochem. Pharmacol. 200, 115028 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Robinson, T. E. & Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47, 33–46 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Bittner, T. et al. γ-Secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J. Neurosci. 29, 10405–10409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Huang, K. W. et al. Molecular and anatomical organization of the dorsal raphe nucleus. eLife 8, e46464 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Olson, D. E. The subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharmacol. Transl. Sci. 4, 563–567 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Yaden, D. B. & Griffiths, R. R. The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacol. Transl. Sci. 4, 568–572 (2020).

  146. Osmond, H. A review of the clinical effects of psychotomimetic agents. Ann. N. Y. Acad. Sci. 66, 418–434 (1957).

    Article  CAS  PubMed  Google Scholar 

  147. Shulgin, A. & Shulgin, A. PIHKAL: A Chemical Love Story (Transform, 1990).

  148. Shulgin, A. & Shulgin, A. TiHKAL: The Continuation (Transform, 2002).

  149. Griffiths, R. R., Richards, W. A., McCann, U. & Jesse, R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology 187, 268–283 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Abramson, H. A. The Use of LSD in Psychotherapy and Alcoholism (Bobbs–Merrill, 1967).

  152. Grob, C. S. et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch. Gen. Psychiatry 68, 71–78 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S. & Duman, R. S. Ketamine: a paradigm shift for depression research and treatment. Neuron 101, 774–778 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Mitchell, J. M. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat. Med. 27, 1025–1033 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Canal, C. E. & Morgan, D. Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test. Anal. 4, 556–576 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Appel, J. B., West, W. B. & Buggy, J. LSD, 5-HT (serotonin), and the evolution of a behavioral assay. Neurosci. Biobehav. Rev. 27, 693–701 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A.C.K. thanks N. Savalia, P. Davoudian and P. Corlett and D.E.O. thanks L. Dunlap, H. Warren and D. Nichols for helpful conversations. A.C.K. was supported by the Yale Program in Psychedelic Science, an One Mind - COMPASS Rising Star Award, and NIH/NIMH grants R01MH121848 and R01MH128217. D.E.O. was supported by NIH/NIDA grant R01DA056365, NIH/NIGMS grant R01GM128997 and the Camille and Henry Dreyfus Foundation. B.L.R. was supported by grants from NIH/NIMH, NIH/NIDA, DARPA and the Michael Hooker Distinguished Professorship.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Alex C. Kwan, David E. Olson, Katrin H. Preller or Bryan L. Roth.

Ethics declarations

Competing interests

A.C.K. is a member of the Scientific Advisory Board of Empyrean Neuroscience and Freedom Biosciences. A.C.K. has consulted for Biohaven Pharmaceuticals. No-cost compounds were provided to A.C.K. for research by Usona Institute. D.E.O. is a cofounder of Delix Therapeutics, Inc., and serves as the Chief Innovation Officer and Head of the Scientific Advisory Board. K.H.P. is currently an employee of Boehringer Ingelheim GmbH & Co. KG. B.L.R. is a member of the Scientific Advisory Board of Septerna Pharmaceuticals and Escient Pharmaceuticals. These duties had no influence on the content of this article.

Peer review

Peer review information

Nature Neuroscience thanks Javier Gonzalez-Maeso, Gitte Knudsen, and Charles Nichols for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwan, A.C., Olson, D.E., Preller, K.H. et al. The neural basis of psychedelic action. Nat Neurosci 25, 1407–1419 (2022). https://doi.org/10.1038/s41593-022-01177-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-022-01177-4

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research