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:

Psychedelics: preclinical insights provide directions for future research

Neuropsychopharmacology volume 49, pages 119–127 (2024)Cite this article

Subjects

Abstract

Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology, pharmacology, and structural biology in an attempt to reveal both the knowns and unknowns within the field.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Overview of the 5-HT (5-HT1-7) family of receptors and their canonical coupling pathways.
Fig. 2: Interactions with the widely used antagonists ketanserin, M100907, and pimavanserin against the 5-HT, dopamine, and alpha-adrenergic receptor families.
Fig. 3: Structures showing the molecular interactions over the entirety of the 5-HT2 family.
Fig. 4: Representative signaling cascades and complexes of the 5-HT2A receptor.
Fig. 5: Representative structures of the various possible interacting proteins with 5-HT2 receptors.

Similar content being viewed by others

References

  1. Nichols DE. Psychedelics. Pharm Rev. 2016;68:264–355. https://doi.org/10.1124/pr.115.011478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McClure-Begley TD, Roth BL. The promises and perils of psychedelic pharmacology for psychiatry. Nat Rev Drug Discov. 2022;21:463–73. https://doi.org/10.1038/s41573-022-00421-7.

    Article  CAS  PubMed  Google Scholar 

  3. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, 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. 2016;30:1181–97. https://doi.org/10.1177/0269881116675513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, 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. 2016;30:1165–80. https://doi.org/10.1177/0269881116675512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78:481–9. https://doi.org/10.1001/jamapsychiatry.2020.3285.

  6. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384:1402–11. https://doi.org/10.1056/NEJMoa2032994.

    Article  CAS  PubMed  Google Scholar 

  7. Holze F, Gasser P, Muller F, Dolder PC, Liechti ME. Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled Phase II study. Biol Psychiatry. 2023;93:215–23. https://doi.org/10.1016/j.biopsych.2022.08.025.

  8. Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387:1637–48. https://doi.org/10.1056/NEJMoa2206443.

    Article  CAS  PubMed  Google Scholar 

  9. Wooley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental disorders. Proc Natl Acad Sci USA. 1954;40:228–31.

    Google Scholar 

  10. Gaddum JH, Hameed KA. Drugs which antagonize 5-hydroxytryptamine. Br J Pharm. 1954;9:240–8.

    CAS  Google Scholar 

  11. Gaddum JH, Khan A, Hathway DE, Stephens FF. Quantitative studies of antagonists for 5-hydroxytryptamine. Q J Exp Physiol. 1955;40:49–74.

    CAS  PubMed  Google Scholar 

  12. Aghjanian GK, Foote WE, Sheard MH. Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science. 1968;161:706–8.

    Google Scholar 

  13. Kelly PH, Iversen LL. LSD as an agonist at mesolimbic dopamine receptors. Psychopharmacologia. 1975;45:221–4.

    CAS  PubMed  Google Scholar 

  14. Geyer MA, Gordon J, Adams LM. Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with LSD. Pharm Biochem Behav. 1985;23:619–25.

    CAS  Google Scholar 

  15. Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharm. 1979;16:687–99.

    CAS  Google Scholar 

  16. Glennon RA, Seggel MR, Soine WH, Herrick-Davis K, Lyon RA, Titeler M. 125I-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI): an iodinated radioligand that specifically labels the agonist high affinity state of the 5HT2 serotonin receptor. J Med Chem. 1988;31:5–7.

    CAS  PubMed  Google Scholar 

  17. Johnson MP, Hoffman AJ, Nichols DE, Mathis CA. Binding to the serotonin 5-HT2 receptor by the enantiomers of 125I-DOI. Neuropharmacology. 1987;26:1803–6. https://doi.org/10.1016/0028-3908(87)90138-9.

    Article  CAS  PubMed  Google Scholar 

  18. Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Giguère PM, et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol. 2015;22:362–9. https://doi.org/10.1038/nsmb.3014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Corne SJ, Pickering RW, Warner BT. A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Br J Pharm Chemother. 1963;20:106–20. https://doi.org/10.1111/j.1476-5381.1963.tb01302.x.

    Article  CAS  Google Scholar 

  20. Malick JB, Doren E, Barnett A. Quipazine-induced head-twitch in mice. Pharm Biochem Behav. 1977;6:325–9.

    CAS  Google Scholar 

  21. Rodriguez R, Pardo EG. Quipazine, a new type of antidepressant agent. Psychopharmacologia. 1971;21:89–100. https://doi.org/10.1007/bf00404000.

    Article  CAS  PubMed  Google Scholar 

  22. Glennon RA, Titler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984;35:2505–11.

    CAS  PubMed  Google Scholar 

  23. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology. 2020;167:107933. https://doi.org/10.1016/j.neuropharm.2019.107933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sanders-Bush E, Burris KD, Knoth K. Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther. 1988;246:924–8.

    CAS  PubMed  Google Scholar 

  25. Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, et al. SAR of psilocybin analogs: discovery of a selective 5-HT(2C) agonist. Bioorg Med Chem Lett. 2005;15:4555–9.

  26. Leysen JE, Niemegeers CJE, Van Nueten JM, Laduron PM. [3H]-ketanserin (R 41 468) a selective 3H-ligand for serotonin2 receptor binding sites. Mol Pharmacol. 1982;21:301–14.

    CAS  PubMed  Google Scholar 

  27. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9:3897–902.

    CAS  PubMed  Google Scholar 

  28. Quednow BB, Kometer M, Geyer MA, Vollenweider FX. Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers. Neuropsychopharmacology. 2012;37:630–40. https://doi.org/10.1038/npp.2011.228.

  29. Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E, Vollenweider FX. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry. 2012;72:898–906. https://doi.org/10.1016/j.biopsych.2012.04.005.

    Article  CAS  PubMed  Google Scholar 

  30. Kometer M, Schmidt A, Jancke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33:10544–51. https://doi.org/10.1523/JNEUROSCI.3007-12.2013.

    Article  CAS  PubMed Central  Google Scholar 

  31. Bernasconi F, Schmidt A, Pokorny T, Kometer M, Seifritz E, Vollenweider FX. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin. Cereb Cortex. 2014;24:3221–31. https://doi.org/10.1093/cercor/bht178.

    Article  Google Scholar 

  32. Pokorny T, Preller KH, Kraehenmann R, Vollenweider FX. 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. 2016;26:756–66. https://doi.org/10.1016/j.euroneuro.2016.01.005.

    Article  CAS  Google Scholar 

  33. Barrett FS, Preller KH, Herdener M, Janata P, Vollenweider FX. Serotonin 2A receptor signaling underlies LSD-induced alteration of the neural response to dynamic changes in music. Cereb Cortex. 2018;28:3939–50. https://doi.org/10.1093/cercor/bhx257.

    Article  Google Scholar 

  34. Preller KH, Burt JB, Ji JL, Schleifer CH, Adkinson BD, Stämpfli P, et al. Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. Elife. 2018;7e35082. https://doi.org/10.7554/eLife.35082.

  35. Abbas A, Roth B. Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmacother. 2008;9:3251–9. https://doi.org/10.1517/14656560802532707.

    Article  CAS  Google Scholar 

  36. Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK, et al. Characterization of the 5-HT2 antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther. 1993;266:684–91.

    CAS  Google Scholar 

  37. Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, et al. Crystal structure of an LSD-bound human serotonin receptor. Cell. 2017;168:377–89.e312. https://doi.org/10.1016/j.cell.2016.12.033.

    Article  CAS  PubMed Central  Google Scholar 

  38. Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE. et al. Structure of a hallucinogen activated gq-coupled 5-HT2A serotonin receptor. Cell. 2020;182:1574–88.e1519. https://doi.org/10.1016/j.cell.2020.08.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, et al. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. 2022;610:582–91. https://doi.org/10.1038/s41586-022-05258-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cao D, Yu J, Wang H, Luo Z, Liu X, He L, et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science. 2022;375:403–11. https://doi.org/10.1126/science.abl8615.

    Article  CAS  Google Scholar 

  41. Cao C, Barros-Álvarez X, Zhang S, Kim K, Dämgen MA, Panova O, et al. Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Neuron. 2022;110:3154–67.e3157. https://doi.org/10.1016/j.neuron.2022.08.006.

    Article  CAS  PubMed Central  Google Scholar 

  42. Gumpper RH, Fay JF, Roth BL. Molecular insights into the regulation of constitutive activity by RNA editing of 5HT(2C) serotonin receptors. Cell Rep. 2022;40:111211. https://doi.org/10.1016/j.celrep.2022.111211.

    Article  CAS  PubMed Central  Google Scholar 

  43. Roth BL, Nakaki T, Chuang DM, Costa E. Aortic recognition sites for serotonin (5HT) are coupled to phospholipase C and modulate phosphatidylinositol turnover. Neuropharmacology. 1984;23:1223–5.

    CAS  Google Scholar 

  44. Conn PJ, Sanders-Bush E. Selective 5-HT2 antagonists inhibit serotonin-stimulated phosphatidylinositol metabolism in cerebral cortex. Neuropharmacology. 1984;23:993–6.

    CAS  Google Scholar 

  45. Leysen JE, De Chaffoy De Courcelles D, De Clerck F, Niemegeers CJE, Van Nueten JM. Serotonin-S2 receptor binding sites and functional correlates. Neuropharmacology. 1984;23:1493–501.

    CAS  Google Scholar 

  46. Roth BL, Nakaki T, Chuang DM, Costa E. 5-Hydroxytryptamine2 receptors coupled to phospholipase C in rat aorta: modulation of phosphoinositide turnover by phorbol ester. J Pharm Exp Ther. 1986;238:480–5.

    CAS  Google Scholar 

  47. Nakaki T, Roth BL, Chuang DM, Costa E. Phasic and tonic components in 5-HT2 receptor-mediated rat aorta contraction: participation of Ca++ channels and phospholipase C. J Pharm Exp Ther. 1985;234:442–6.

    CAS  Google Scholar 

  48. Gray JA, Compton-Toth BA, Roth BL. Identification of two serine residues essential for agonist-induced 5-HT2A receptor desensitization. Biochemistry. 2003;42:10853–62.

    CAS  Google Scholar 

  49. Gelber EI, Kroeze WK, Willins DL, Gray JA, Sinar CA, Hyde EG, et al. Structure and function of the third intracellular loop of the 5-hydroxytryptamine(2A) receptor: the third intracellular loop is alpha-helical and binds purified arrestins. J Neurochem. 1999;72:2206–14.

    CAS  Google Scholar 

  50. Gray J, Bhatnagar A, Gurevich V, Roth B. The interaction of a constitutively active arrestin with the arrestin-insensitive 5-HT2A receptor induces agonist-independent internalization. Mol Pharmacol. 2003;63:961–72.

    CAS  Google Scholar 

  51. Strachan RT, Sheffler DJ, Willard B, Kinter M, Kiselar JG, Roth BL. Ribosomal S6 kinase 2 directly phosphorylates the 5-HT2A serotonin receptor thereby modulating 5-HT2A signaling. J Biol Chem. 2009;284:5557–73. https://doi.org/10.1074/jbc.M805705200.

  52. Sheffler DJ, Kroeze WK, Garcia BG, Deutch AY, Hufeisen SJ, Leahy P, et al. p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci USA. 2006;103:4717–22.

    CAS  PubMed Central  Google Scholar 

  53. Strachan RT, Allen JA, Sheffler DJ, Roth BL. p90 Ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling. Biochemistry. 2010;49:2657–71. https://doi.org/10.1021/bi901921k.

    Article  CAS  Google Scholar 

  54. Strachan RT, Sciaky N, Cronan MR, Kroeze WK, Roth BL. Genetic deletion of p90 ribosomal S6 kinase 2 alters patterns of 5-hydroxytryptamine 2A serotonin receptor functional selectivity. Mol Pharm. 2010;77:327–38. https://doi.org/10.1124/mol.109.061440.

    Article  CAS  Google Scholar 

  55. Garcia EE, Smith RL, Sanders-Bush E. Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology. 2007;52:1671–7. https://doi.org/10.1016/j.neuropharm.2007.03.013.

    Article  CAS  PubMed Central  Google Scholar 

  56. Rodriguiz RM, Nadkarni V, Means CR, Pogorelov VM, Chiu YT, Roth BL, et al. LSD-stimulated behaviors in mice require beta-arrestin 2 but not beta-arrestin 1. Sci Rep. 2021;11:17690. https://doi.org/10.1038/s41598-021-96736-3.

    Article  CAS  PubMed Central  Google Scholar 

  57. Lucaites VL, Nelson DL, Wainscott DB, Baez M. Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily. Life Sci. 1996;59:1081–95. https://doi.org/10.1016/0024-3205(96)00423-7.

    Article  CAS  Google Scholar 

  58. Zhang JY, Ashby CR Jr, Wang RY. Effect of pertussis toxin on the response of rat medial prefrontal cortex cells to the iontophoresis of serotonin receptor agonists. J Neural Transm Gen Sect. 1994;95:165–72. https://doi.org/10.1007/BF01271563.

    Article  CAS  Google Scholar 

  59. Schmitz GP, Chiu YT, König GM, Kostenis E, Roth BL, Herman MA. Psychedelic compounds directly excite 5-HT2A layer 5 pyramidal neurons in the prefrontal cortex through a 5-HT2A Gq-mediated activation mechanism. bioRxiv [Preprint]. 2022 2022.2011.2015.516655. https://doi.org/10.1101/2022.11.15.516655.

  60. Garnovskaya MN, Nebigil CG, Arthur JM, Spurney RF, Raymond JR. 5-Hydroxytryptamine2A receptors expressed in rat renal mesangial cells inhibit cyclic AMP accumulation. Mol Pharm. 1995;48:230–7.

    CAS  Google Scholar 

  61. González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–52.

    PubMed  Google Scholar 

  62. Cornea-Hébert V, Watkins KC, Roth BL, Kroeze WK, Gaudreau P, Leclerc N, et al. Similar ultrastructural distribution of the 5-HT2A serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat. Neuroscience. 2002;113:23–35.

    PubMed  Google Scholar 

  63. Xia Z, Gray J, Compton-Toth B, Roth B. A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem. 2003;278:21901–8. https://doi.org/10.1074/jbc.M301905200.

    Article  CAS  PubMed  Google Scholar 

  64. Abbas AI, Yadav PN, Yao WD, Arbuckle MI, Grant SG, Caron MG, et al. PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci. 2009;29:7124–36. https://doi.org/10.1523/JNEUROSCI.1090-09.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci USA. 2009;106:19575–80. https://doi.org/10.1073/pnas.0905884106.

  66. Bhatnagar A, Sheffler D, Kroeze W, Compton-Toth B, Roth B. Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected G alpha(q)-coupled protein receptors. J Biol Chem. 2004;279:34614–23. https://doi.org/10.1074/jbc.M404673200.

    Article  CAS  Google Scholar 

  67. Allen JA, Yadav PN, Setola V, Farrell M, Roth BL. Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo. Transl Psych. 2011;1:e33 https://doi.org/10.1038/tp.2011.35.

    Article  CAS  Google Scholar 

  68. Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci USA. 2009;106:19575–80. https://doi.org/10.1073/pnas.0905884106.

    Article  PubMed Central  Google Scholar 

  69. Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23:3170–82. https://doi.org/10.1016/j.celrep.2018.05.022.

    Article  CAS  PubMed Central  Google Scholar 

  70. Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021;109:2535–44.e2534. https://doi.org/10.1016/j.neuron.2021.06.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Johnson MP, Loncharich RJ, Baez M, Nelson DL. Species variations in transmembrane region V of the 5-hydroxytryptamine type 2A receptor alter the structure-activity relationship of certain ergolines and tryptamines. Mol Pharm. 1994;45:277–86.

    CAS  Google Scholar 

  72. Johnson MP, Baez M, Kursar JD, Nelson DL. Species differences in 5-HT2A receptors: cloned pig and rhesus monkey 5-HT2A receptors reveal conserved transmembrane homology to the human rather than rat sequence. Biochim Biophys Acta. 1995;1236:201–6.

    PubMed  Google Scholar 

  73. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43. https://doi.org/10.1038/s41586-020-2308-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Davies MA, Setola V, Strachan RT, Sheffler DJ, Salay E, Hufeisen SJ, et al. Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006;6:42–51. https://doi.org/10.1038/sj.tpj.6500342.

    Article  CAS  PubMed  Google Scholar 

  75. Schmitz GP, Jain MK, Slocum ST, Roth BL. 5-HT(2A) SNPs alter the pharmacological signaling of potentially therapeutic psychedelics. ACS Chem Neurosci. 2022;13:2386–98. https://doi.org/10.1021/acschemneuro.1c00815.

    Article  CAS  PubMed  Google Scholar 

  76. Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Giguère PM, et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol. 2015;22:362–9. https://doi.org/10.1038/nsmb.3014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ray TS. Psychedelics and the human receptorome. PLoS One. 2010;5:e9019. https://doi.org/10.1371/journal.pone.0009019.

  78. Cameron LP, Patel SD, Vargas MV, Barragan EV, Saeger HN, Warren HT, et al. 5-HT2ARs mediate therapeutic behavioral effects of psychedelic tryptamines. ACS Chem Neurosci. 2023;14:351–8. https://doi.org/10.1021/acschemneuro.2c00718.

  79. de la Fuente Revenga M, Zhu B, Guevara CA, Naler LB, Saunders JM, Zhou Z, et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 2021;37:109836. https://doi.org/10.1016/j.celrep.2021.109836.

    Article  CAS  PubMed  Google Scholar 

  80. Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci USA. 2021;118:e2022489118. https://doi.org/10.1073/pnas.2022489118.

  81. Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, et al. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist. Bioorg Med Chem Lett. 2005;15:4555–9.

    CAS  PubMed  Google Scholar 

  82. Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, et al. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment. Mol Pharm. 2009;76:710–22. https://doi.org/10.1124/mol.109.058057.

    Article  CAS  Google Scholar 

  83. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–41.

    CAS  PubMed  Google Scholar 

  84. Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharm. 2000;57:75–81.

    CAS  Google Scholar 

  85. Roth BL. Drugs and valvular heart disease. N Engl J Med. 2007;356:6–9.

    CAS  PubMed  Google Scholar 

  86. Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharm. 2003;63:1223–9.

    CAS  Google Scholar 

  87. Connolly HM, McGoon MD. Obesity drugs and the heart. Curr Probl Cardiol. 1999;24:745–92.

    CAS  PubMed  Google Scholar 

  88. Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007;356:39–46.

    CAS  PubMed  Google Scholar 

  89. Montastruc F, Montastruc G, Vigreux P, Bruneval P, Guilbeau-Frugier C, Cron C, et al. Valvular heart disease in a patient taking 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’). Br J Clin Pharm. 2012;74:547–8. https://doi.org/10.1111/j.1365-2125.2012.04252.x.

    Article  Google Scholar 

  90. Droogmans S, Cosyns B, D’haenen H, Creeten E, Weytjens C, Franken PR, et al. Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease. Am J Cardiol. 2007;100:1442–5. https://doi.org/10.1016/j.amjcard.2007.06.045.

    Article  CAS  PubMed  Google Scholar 

  91. Cavero I, Guillon JM. Safety pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy. J Pharm Toxicol Methods. 2014;69:150–61. https://doi.org/10.1016/j.vascn.2013.12.004.

    Article  CAS  Google Scholar 

  92. Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, et al. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes. J Pharm Exp Ther. 2002;303:815–22.

    CAS  Google Scholar 

  93. Willins DL, Meltzer HY. Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharm Exp Ther. 1997;282:699–706.

    CAS  Google Scholar 

  94. Griffith JD, Nutt JG, Jasinski DR. A comparison of fenfluramine and amphetamine in man. Clin Pharm Ther. 1975;18:563–70. https://doi.org/10.1002/cpt1975185part1563.

    Article  CAS  Google Scholar 

  95. Koreen AR, Lieberman JA, Alvir J, Chakos M. The behavioral effect of m-chlorophenylpiperazine (mCPP) and methylphenidate in first-episode schizophrenia and normal controls. Neuropsychopharmacology. 1997;16:61–68. https://doi.org/10.1016/S0893-133X(96)00160-1.

    Article  CAS  PubMed  Google Scholar 

  96. Parkes JD, Marsden CD, Donaldson I, Galea-Debono A, Walters J, Kennedy G, et al. Bromocriptine treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1976;39:184–93. https://doi.org/10.1136/jnnp.39.2.184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Knoll J, Vizi ES. Cross-tolerance between para-bromo-methamphetamine (V-111) and LSD-25. Pharmacology. 1970;4:278–86.

    CAS  PubMed  Google Scholar 

  98. Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021;589:474–9. https://doi.org/10.1038/s41586-020-3008-z.

    Article  CAS  PubMed  Google Scholar 

  99. Levit Kaplan A, Strachan RT, Braz JM, Craik V, Slocum S, Mangano T, et al. Structure-based design of a chemical probe set for the 5-HT5A serotonin receptor. J Med Chem. 2022;65:4201–17. https://doi.org/10.1021/acs.jmedchem.1c02031.

    Article  CAS  PubMed  Google Scholar 

  100. Kwan AC, Olson DE, Preller KH, Roth BL. The neural basis of psychedelic action. Nat Neurosci. 2022;25:1407–19. https://doi.org/10.1038/s41593-022-01177-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Casey AB, Cui M, Booth RG, Canal CE. “Selective” serotonin 5-HT(2A) receptor antagonists. Biochem Pharm. 2022;200:115028 https://doi.org/10.1016/j.bcp.2022.115028.

    Article  CAS  PubMed  Google Scholar 

  102. Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PAJ. Non-serotonergic [3H]-ketanserin binding sites in striatal membranes are associated with a dopac release system on dopaminergic nerve endings. Eur J Pharm. 1987;134:373–5.

    CAS  Google Scholar 

  103. Roth BL, McLean S, Zhu XZ, Chuang DM. Characterization of two [3H]ketanserin recognition sites in rat striatum. J Neurochem. 1987;49:1833–8.

    CAS  PubMed  Google Scholar 

  104. Felder CC, Kanterman RY, Ma AL, 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. 1990;87:2187–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Berg KA, Maayani S, Goldfarb J, Clarke WP. Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists. Ann N Y Acad Sci. 1998;861:104–10.

    CAS  PubMed  Google Scholar 

  106. Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP. Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharm. 1998;54:94–104.

    CAS  Google Scholar 

  107. Kurrasch-Orbaugh DM, Watts VJ, Barker EL, Nichols DE. Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves. J Pharm Exp Ther. 2003;304:229–37.

    CAS  Google Scholar 

  108. González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008;452:93–7. https://doi.org/10.1038/nature06612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493:76–9. https://doi.org/10.1016/j.neulet.2011.01.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuéllar F, et al. Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem. 2012;287:44301–19. https://doi.org/10.1074/jbc.M112.413161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, et al. Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology. 2012;62:2184–91. https://doi.org/10.1016/j.neuropharm.2012.01.010.

    Article  CAS  PubMed  Google Scholar 

  112. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA. 2007;104:5163–8.

    PubMed  PubMed Central  Google Scholar 

  113. Nagai Y, Miyakawa N, Takuwa H, Hori Y, Oyama K, Ji B, et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat Neurosci. 2020;23:1157–67. https://doi.org/10.1038/s41593-020-0661-3.

  114. Zhang S, Gumpper RH, Huang XP, Liu Y, Krumm BE, Cao C, et al. Molecular basis for selective activation of DREADD-based chemogenetics. Nature. 2022;612:354–62. https://doi.org/10.1038/s41586-022-05489-0.

  115. Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharm Exp Ther. 2008;327:316–23. https://doi.org/10.1124/jpet.108.143461.

    Article  CAS  Google Scholar 

  116. Grailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X, Brunner D, et al. Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor. Neuron. 1999;22:581–91.

    CAS  PubMed  Google Scholar 

  117. Marona-Lewicka D, Thisted RA, Nichols DE. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology (Berl). 2005;180:427–35. https://doi.org/10.1007/s00213-005-2183-9.

    Article  CAS  PubMed  Google Scholar 

  118. Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, et al. Inactive and active state structures template selective tools for the human 5-HT5A receptor. Nat Struct Mol Biol. 2022;29:677–87. https://doi.org/10.1038/s41594-022-00796-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Miner LA, Backstrom JR, Sanders-Bush E, Sesack SR. Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience. 2003;116:107–17.

    CAS  PubMed  Google Scholar 

  120. Xia Z, Hufeisen SJ, Gray JA, Roth BL. The PDZ-binding domain is essential for the dendritic targeting of 5-HT(2A) serotonin receptors in cortical pyramidal neurons in vitro. Neuroscience. 2003;122:907–20.

    CAS  PubMed  Google Scholar 

  121. Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078. https://doi.org/10.1126/science.aat8078.

  122. Hajszan T, MacLusky NJ, Leranth C. Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. Eur J Neurosci. 2005;21:1299–303. https://doi.org/10.1111/j.1460-9568.2005.03968.x.

    Article  PubMed  Google Scholar 

  123. Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron. 2003;38:157–60.

    CAS  PubMed  Google Scholar 

  124. Duman RS. Neuropharmacology in the next millennium: promise for breakthrough discoveries [editorial]. Neuropsychopharmacology. 1999;20:97–8.

    CAS  PubMed  Google Scholar 

  125. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996–1005. https://doi.org/10.1016/j.biopsych.2011.09.030.

    Article  CAS  PubMed  Google Scholar 

  126. Gewirtz JC, Chen AC, Terwilliger R, Duman RC, Marek GJ. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharm Biochem Behav. 2002;73:317–26.

    CAS  Google Scholar 

  127. Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, et al. Pharmacological mechanism of the non-hallucinogenic 5-HT(2A) agonist ariadne and analogs. ACS Chem Neurosci. 2022;14:119–35. https://doi.org/10.1021/acschemneuro.2c00597.

    Article  CAS  PubMed  Google Scholar 

  128. Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. Cephalalgia. 2010;30:1140–4. https://doi.org/10.1177/0333102410363490.

    Article  PubMed  Google Scholar 

  129. Hougaku H, Matsumoto M, Hata R, Handa N, Imaizumi M, Sugitani Y. et al. [Therapeutic effect of lisuride maleate on post-stroke depression]. Nihon Ronen Igakkai Zasshi. 1994;31:52–9. https://doi.org/10.3143/geriatrics.31.52.

    CAS  PubMed  Google Scholar 

  130. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–9. https://doi.org/10.1038/s41586-021-03819-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Work in the Roth lab is supported by grants from the NIH and DARPA to BLR as well as the Michael Hooker Distinguished Professorship.

Author information

Authors and Affiliations

  1. Department of Pharmacology, UNC School of Medicine, Chapel Hill, NC, 27514, USA

    Ryan H. Gumpper & Bryan L. Roth

Authors
  1. Ryan H. Gumpper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bryan L. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BLR and RHG jointly wrote the paper and created the figures.

Corresponding author

Correspondence to Bryan L. Roth.

Ethics declarations

Competing interests

BLR is a member of the Scientific Advisory Boards of Septerna Pharmaceuticals, Escient Pharmaceuticals and Onsero, Inc. As well, BLR is a scientific co-founder of Onsero and is listed as an inventor on patents related to the research in this review article. RHG declares no conflicts.

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 (e.g. a society or other partner) 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

Gumpper, R.H., Roth, B.L. Psychedelics: preclinical insights provide directions for future research. Neuropsychopharmacol. 49, 119–127 (2024). https://doi.org/10.1038/s41386-023-01567-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01567-7

This article is cited by

Search

Advanced search

Quick links