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Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects

Molecular Psychiatry volume 30, pages 5926–5937 (2025)Cite this article

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Abstract

Serotonergic psychedelics, including the recreationally used psilocybin and LSD, have become promising therapeutic agents for the treatment of treatment-resistant depression. While it is generally agreed that they exhibit their antidepressant effects by inducing rapid and sustained neuroplasticity, the molecular mechanisms responsible are widely debated. In particular, the role of the serotonin 5-HT2A receptor, known to mediate the hallucinogenic effects of psychedelics, is under scrutiny. However, many studies remain in conflict on whether action at the receptor is also required for neuroplastic effects. In this narrative review, we examine the available evidence for the involvement of the 5-HT2A receptor in neuroplasticity induction and the possibly antidepressant effects of psychedelics. Firstly, we review the role of decreased neuroplasticity in depression, the evidence for dendrito-, spino- and synaptogenesis promotion by psychedelics, and for its possible regional selectivity. We then discuss the current knowledge on psychedelic action at the 5-HT2A receptor, including its role in promoting hallucinogenic effects. Finally, we critically assess the studies testing the necessity for 5-HT2A signalling for neuroplastic effects and present a model of molecular mechanisms responsible for psychedelic-induced neuroplasticity.

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Fig. 1: The possible molecular mechanisms behind psychedelic-induced neuroplasticity.

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References

  1. Sessa B. Shaping the renaissance of psychedelic research. The Lancet. 2012;380:200–1.

    Google Scholar 

  2. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68:264–355.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. 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.

    PubMed  Google Scholar 

  4. Goodwin GM, Croal M, Feifel D, Kelly JR, Marwood L, Mistry S, et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2023;48:1492–9.

    CAS  Google Scholar 

  5. Results Posted | A Double-Blind Trial of Psilocybin-Assisted Treatment of Alcohol Dependence | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02061293. Accessed 15 July 2024.

  6. Study Details | LSD Treatment for Persons With Alcohol Use Disorder | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05474989. Accessed 15 July 2024.

  7. Study Details | Psilocybin-Assisted Psychotherapy in Adults With Alcohol Use Disorder (AUD) | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05646303. Accessed 15 July 2024.

  8. Study Details | Psilocybin as a Treatment for Anorexia Nervosa: A Pilot Study | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04505189. Accessed 15 July 2024.

  9. Study Details | Evaluation of Psilocybin in Anorexia Nervosa: Safety and Efficacy | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04661514. Accessed 15 July 2024.

  10. Study Details | Psilocybin in Co-occuring Major Depressive Disorder and Borderline Personality Disorder | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05399498. Accessed 15 July 2024.

  11. Study Details | The Safety and Tolerability of COMP360 in Participants With Post-traumatic Stress Disorder | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05312151. Accessed 15 July 2024.

  12. Study Details | Phase 2 Clinical Trial of GH001 in Bipolar II Disorder | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05839509. Accessed 15 July 2024.

  13. Study Details | Outpatient Buprenorphine Induction With Psilocybin for Opioid Use Disorder | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT06067737. Accessed 15 July 2024.

  14. Study Details | Psilocybin-facilitated Smoking Cessation Treatment: A Pilot Study | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT01943994. Accessed 15 July 2024.

  15. Study Details | A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of up to Two Doses of Psilocybin for the Treatment of Major Depressive Disorder in Adults With Cancer | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05947383. Accessed 15 July 2024.

  16. Results Posted | Psychopharmacology of Psilocybin in Cancer Patients | ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT00465595. Accessed 15 July 2024.

  17. Olson DE. Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J Exp Neurosci. 2018;12:1179069518800508.

    PubMed  PubMed Central  Google Scholar 

  18. Drevets WC, Ongür D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3:220–6.

    PubMed  CAS  Google Scholar 

  19. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry. 2000;48:813–29.

    PubMed  CAS  Google Scholar 

  20. Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024;9:1–32.

    CAS  Google Scholar 

  21. Molendijk ML, Bus BAA, Spinhoven P, Penninx BWJH, Kenis G, Prickaerts J, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011;16:1088–95.

    PubMed  CAS  Google Scholar 

  22. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–10.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Olson DE. The Subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci. 2021;4:563–7.

    PubMed  CAS  Google Scholar 

  24. Yaden DB, Griffiths RR. The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci. 2021;4:568–72.

    PubMed  CAS  Google Scholar 

  25. Lewis V, Bonniwell EM, Lanham JK, Ghaffari A, Sheshbaradaran H, Cao AB, et al. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Rep. 2023;42:112203.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. 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.

    PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  CAS  Google Scholar 

  28. Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, et al. Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications. Int J Mol Sci. 2022;23:14148.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. 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.

    PubMed  CAS  Google Scholar 

  30. Desouza LA, Benekareddy M, Fanibunda SE, Mohammad F, Janakiraman B, Ghai U, et al. The hallucinogenic Serotonin2A receptor agonist, 2,5-Dimethoxy-4-Iodoamphetamine, promotes cAMP response element binding protein-dependent gene expression of specific plasticity-associated genes in the rodent neocortex. Front Mol Neurosci. 2021;14:790213.

    PubMed  PubMed Central  CAS  Google Scholar 

  31. Shao L-X, 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;109:2535–2544.e4.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Revenga M, de la F, 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.

    PubMed Central  Google Scholar 

  34. Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17:2785–95.

    PubMed  PubMed Central  CAS  Google Scholar 

  35. Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science. 2023. 17 February 2023. https://doi.org/10.1126/science.adf0435.

  36. 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. 2021;118:e2022489118.

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci. 2023;26:1032–41.

    PubMed  PubMed Central  Google Scholar 

  38. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    PubMed  Google Scholar 

  39. Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ. 2022;378:e067606.

    PubMed  PubMed Central  Google Scholar 

  40. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47–53.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, et al. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010;53:4731–48.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Wang H-Q, Wang Z-Z, Chen N-H. The receptor hypothesis and the pathogenesis of depression: Genetic bases and biological correlates. Pharmacol Res. 2021;167:105542.

    PubMed  CAS  Google Scholar 

  43. Stahl SM. Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications. 4th ed. New York, NY, US: Cambridge University Press; 2013.

    Google Scholar 

  44. Undurraga J, Baldessarini RJ. Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-to-head trials in acute major depression: Systematic review and meta-analysis. J Psychopharmacol (Oxf). 2017;31:1184–9.

    CAS  Google Scholar 

  45. Haase J, Brown E. Integrating the monoamine, neurotrophin and cytokine hypotheses of depression — A central role for the serotonin transporter? Pharmacol Ther. 2015;147:1–11.

    PubMed  CAS  Google Scholar 

  46. Oquendo MA, Placidi GPA, Malone KM, Campbell C, Keilp J, Brodsky B, et al. Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression. Arch Gen Psychiatry. 2003;60:14–22.

    PubMed  Google Scholar 

  47. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci. 1992;12:3628–41.

    PubMed  PubMed Central  CAS  Google Scholar 

  48. Liu W, Ge T, Leng Y, Pan Z, Fan J, Yang W, et al. The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural Plast. 2017;2017:6871089.

    PubMed  PubMed Central  Google Scholar 

  49. Chan SWY, Harmer CJ, Norbury R, O’Sullivan U, Goodwin GM, Portella MJ. Hippocampal volume in vulnerability and resilience to depression. J Affect Disord. 2016;189:199–202.

    PubMed  Google Scholar 

  50. Bartkowska K, Paquin A, Gauthier AS, Kaplan DR, Miller FD. Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development. Development. 2007;134:4369–80.

    PubMed  CAS  Google Scholar 

  51. Minichiello L. TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 2009;10:850–60.

    PubMed  CAS  Google Scholar 

  52. Bus BaA, Molendijk ML, Tendolkar I, Penninx BWJH, Prickaerts J, Elzinga BM, et al. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time. Mol Psychiatry. 2015;20:602–8.

    PubMed  CAS  Google Scholar 

  53. Talaee N, Azadvar S, Khodadadi S, Abbasi N, Asli-Pashaki ZN, Mirabzadeh Y, et al. Comparing the effect of fluoxetine, escitalopram, and sertraline, on the level of BDNF and depression in preclinical and clinical studies: a systematic review. Eur J Clin Pharmacol. 2024;80:983–1016.

    PubMed  Google Scholar 

  54. Madsen CA, Navarro ML, Elfving B, Kessing LV, Castrén E, Mikkelsen JD, et al. The effect of antidepressant treatment on blood BDNF levels in depressed patients: a review and methodological recommendations for assessment of BDNF in blood. Eur Neuropsychopharmacol. 2024;87:35–55.

    PubMed  CAS  Google Scholar 

  55. Ray MT, Shannon Weickert C, Webster MJ. Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry. 2014;4:e389.

    PubMed  PubMed Central  CAS  Google Scholar 

  56. Rahmani F, Saghazadeh A, Rahmani M, Teixeira AL, Rezaei N, Aghamollaii V, et al. Plasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: a systematic review and meta-analysis. Brain Res. 2019;1704:127–36.

    PubMed  CAS  Google Scholar 

  57. Kim OY, Song J. The importance of BDNF and RAGE in diabetes-induced dementia. Pharmacol Res. 2020;160:105083.

    PubMed  CAS  Google Scholar 

  58. Davarpanah M, Shokri-mashhadi N, Ziaei R, Saneei P. A systematic review and meta-analysis of association between brain-derived neurotrophic factor and type 2 diabetes and glycemic profile. Sci Rep. 2021;11:1–14.

    Google Scholar 

  59. Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet. 2007;369:1047–53.

    Google Scholar 

  60. Yanagita T. Intravenous self-administration of (−)-cathinone and 2-amino-1-(2,5-dimethoxy-4-methyl)phenylpropane in rhesus monkeys. Drug Alcohol Depend. 1986;17:135–41.

    PubMed  CAS  Google Scholar 

  61. Deneau G, Yanagita T, Seevers MH. Self-administration of psychoactive substances by the monkey. Psychopharmacologia. 1969;16:30–48.

    PubMed  CAS  Google Scholar 

  62. Becker AM, Klaiber A, Holze F, Istampoulouoglou I, Duthaler U, Varghese N, et al. Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy participants. Int J Neuropsychopharmacol. 2023;26:97–106.

    PubMed  CAS  Google Scholar 

  63. Kometer M, Schmidt A, Jäncke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33:10544–51.

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2021;46:537–44.

    PubMed  CAS  Google Scholar 

  65. Valle M, Maqueda AE, Rabella M, Rodríguez-Pujadas A, Antonijoan RM, Romero S, et al. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. Eur Neuropsychopharmacol. 2016;26:1161–75.

    PubMed  CAS  Google Scholar 

  66. 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.

    PubMed  CAS  Google Scholar 

  67. Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport. 1998;9:3897.

    PubMed  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Stämpfli P, et al. The fabric of meaning and subjective effects in LSD-Induced states depend on serotonin 2A receptor activation. Curr Biol. 2017;27:451–7.

    PubMed  CAS  Google Scholar 

  70. Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, et al. Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects. Transl Psychiatry. 2024;14:1–8.

    Google Scholar 

  71. Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, et al. Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: relevance for psychedelic research. Eur Neuropsychopharmacol. 2024;88:43–48.

    PubMed  CAS  Google Scholar 

  72. Casey AB, Cui M, Booth RG, Canal CE. “Selective” serotonin 5-HT2A receptor antagonists. Biochem Pharmacol. 2022;200:115028.

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbæk DS, Kristiansen S, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019;44:1328–34.

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Corne SJ, Pickering RW. A possible correlation between drug-induced hallucinations in man and a behavioural response in mice. Psychopharmacologia. 1967;11:65–78.

    PubMed  CAS  Google Scholar 

  75. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Fiorella D, Rabin RA, Winter JC. The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs I: Antagonist correlation analysis. Psychopharmacology (Berl). 1995;121:347–56.

    PubMed  CAS  Google Scholar 

  77. Halberstadt AL, Koedood L, Powell SB, Geyer MA. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J Psychopharmacol (Oxf). 2011;25:1548–61.

    CAS  Google Scholar 

  78. Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC. The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology (Berl). 2010;209:163–74.

    PubMed  CAS  Google Scholar 

  79. Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, et al. Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS Pharmacol Transl Sci. 2021;4:461–6.

    PubMed  CAS  Google Scholar 

  80. de Almeida RN, de Galvão ACM, da Silva FS, Silva EADS, Palhano-Fontes F, Maia-de-Oliveira JP, et al. Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca: observation from a randomized controlled trial. Front Psychol. 2019;10:1234.

    PubMed  PubMed Central  Google Scholar 

  81. Becker AM, Holze F, Grandinetti T, Klaiber A, Toedtli VE, Kolaczynska KE, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther. 2022;111:886–95.

    PubMed  CAS  Google Scholar 

  82. Holze F, Ley L, Müller F, Becker AM, Straumann I, Vizeli P, et al. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2022;47:1180–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  83. Holze F, Vizeli P, Müller F, Ley L, Duerig R, Varghese N, et al. Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacology. 2020;45:462–71.

    PubMed  CAS  Google Scholar 

  84. Rocha JM, Rossi GN, de Lima Osório F, Bouso JC, de Oliveira Silveira G, Yonamine M, et al. Effects of ayahuasca on the recognition of facial expressions of emotions in naive healthy volunteers: a pilot, proof-of-concept, randomized controlled trial. J Clin Psychopharmacol. 2021;41:267.

    PubMed  Google Scholar 

  85. Vogt SB, Ley L, Erne L, Straumann I, Becker AM, Klaiber A, et al. Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants. Transl Psychiatry. 2023;13:172.

    PubMed  PubMed Central  CAS  Google Scholar 

  86. Shafiee A, Arabzadeh Bahri R, Rafiei MA, Esmaeilpur Abianeh F, Razmara P, Jafarabady K, et al. The effect of psychedelics on the level of brain-derived neurotrophic factor: a systematic review and meta-analysis. J Psychopharmacol (Oxf). 2024;38:425–31.

    Google Scholar 

  87. Le Nedelec M, Glue P, Winter H, Goulton C, Broughton L, Medlicott N. Acute low-dose ketamine produces a rapid and robust increase in plasma BDNF without altering brain BDNF concentrations. Drug Deliv Transl Res. 2018;8:780–6.

    PubMed  Google Scholar 

  88. Ly C, Greb AC, Vargas MV, Duim WC, Grodzki ACG, Lein PJ, et al. Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacol Transl Sci. 2021;4:452–60.

    PubMed  CAS  Google Scholar 

  89. Raval NR, Johansen A, Donovan LL, Ros NF, Ozenne B, Hansen HD, et al. A Single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci. 2021;22:835.

    PubMed  PubMed Central  CAS  Google Scholar 

  90. Zhao X, Du Y, Yao Y, Dai W, Yin Y, Wang G, et al. Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice. J Psychopharmacol (Oxf). 2024;38:489–99.

    CAS  Google Scholar 

  91. Calder AE, Hasler G. Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology. 2023;48:104–12.

    PubMed  Google Scholar 

  92. Benekareddy M, Nair AR, Dias BG, Suri D, Autry AE, Monteggia LM, et al. Induction of the plasticity-Associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol. 2013;16:405–15.

    PubMed  CAS  Google Scholar 

  93. Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med. 1998;39:208–14.

    PubMed  CAS  Google Scholar 

  94. Beliveau V, Ganz M, Feng L, Ozenne B, Højgaard L, Fisher PM, et al. A High-Resolution in vivo atlas of the human brain’s serotonin system. J Neurosci. 2017;37:120–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  95. Pompeiano M, Palacios JM, Mengod G. Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Mol Brain Res. 1994;23:163–78.

    PubMed  CAS  Google Scholar 

  96. Davoudian PA, Shao L-X, Kwan AC. Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin. ACS Chem Neurosci. 2023;14:468–80.

    PubMed  CAS  Google Scholar 

  97. Korpi ER, den Hollander B, Farooq U, Vashchinkina E, Rajkumar R, Nutt DJ, et al. Mechanisms of action and persistent neuroplasticity by drugs of abuse. Pharmacol Rev. 2015;67:872–1004.

    PubMed  CAS  Google Scholar 

  98. Tuvikene J, Pruunsild P, Orav E, Esvald E-E, Timmusk T. AP-1 Transcription factors mediate BDNF-Positive feedback loop in cortical neurons. J Neurosci. 2016;36:1290–305.

    PubMed  PubMed Central  CAS  Google Scholar 

  99. López-Giménez JF, González-Maeso J Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways. In: Halberstadt AL, Vollenweider FX, Nichols DE, editors. Behav. Neurobiol. Psychedelic Drugs, Berlin, Heidelberg: Springer; 2018. p. 45–73.

  100. Rantamäki T. TrkB neurotrophin receptor at the core of antidepressant effects, but how? Cell Tissue Res. 2019;377:115–24.

    PubMed  Google Scholar 

  101. Luttrell LM, Lefkowitz RJ. The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci. 2002;115:455–65.

    PubMed  CAS  Google Scholar 

  102. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018;17:243–60.

    PubMed  PubMed Central  CAS  Google Scholar 

  103. 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;182:1574–1588.e19.

    PubMed  PubMed Central  CAS  Google Scholar 

  104. Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, et al. Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nat Commun. 2023;14:8221.

    PubMed  PubMed Central  CAS  Google Scholar 

  105. Glatfelter GC, Pottie E, Partilla JS, Stove CP, Baumann MH. Comparative pharmacological effects of lisuride and lysergic acid diethylamide revisited. ACS Pharmacol Transl Sci. 2024;7:641–53.

    PubMed  PubMed Central  CAS  Google Scholar 

  106. Rodriguiz RM, Nadkarni V, Means CR, Pogorelov VM, Chiu Y-T, Roth BL, et al. LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1. Sci Rep. 2021;11:1–14.

    Google Scholar 

  107. Schmid CL, Raehal KM, Bohn LM. Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo. Proc Natl Acad Sci. 2008;105:1079–84.

    PubMed  PubMed Central  CAS  Google Scholar 

  108. Schmid CL, Bohn LM. Serotonin, but not N-Methyltryptamines, activates the serotonin 2A receptor via a β-Arrestin2/Src/Akt signaling complex in vivo. J Neurosci. 2010;30:13513–24.

    PubMed  PubMed Central  CAS  Google Scholar 

  109. Smith RL, Barrett RJ, Sanders-Bush E. Neurochemical and behavioral evidence that quipazine-ketanserin discrimination is mediated by serotonin2A receptor. J Pharmacol Exp Ther. 1995;275:1050–7.

    PubMed  CAS  Google Scholar 

  110. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Marek GJ, Martin-Ruiz R, Abo A, Artigas F. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology. 2005;30:2205–15.

    PubMed  CAS  Google Scholar 

  112. Liu J-L, Li M, Dang X-R, Wang Z-H, Rao Z-R, Wu S-X, et al. A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a pavlovian model. PLOS ONE. 2009;4:e7548.

    PubMed  PubMed Central  Google Scholar 

  113. Dalton GL, Wu DC, Wang YT, Floresco SB, Phillips AG. NMDA GluN2A and GluN2B receptors play separate roles in the induction of LTP and LTD in the amygdala and in the acquisition and extinction of conditioned fear. Post-Trauma Stress Disord. 2012;62:797–806.

    CAS  Google Scholar 

  114. Planchez B, Surget A, Belzung C. Animal models of major depression: drawbacks and challenges. J Neural Transm. 2019;126:1383–408.

    PubMed  CAS  Google Scholar 

  115. Belovicova K, Bogi E, Csatlosova K, Dubovicky M. Animal tests for anxiety-like and depression-like behavior in rats. Interdiscip Toxicol. 2017;10:40–43.

    PubMed  Google Scholar 

  116. Hendrie C, Pickles A. The failure of the antidepressant drug discovery process is systemic. J Psychopharmacol (Oxf). 2013;27:407–16.

    Google Scholar 

  117. Pehrson AL, Roberts D, Khawaja A, McNair R. The role of serotonin neurotransmission in rapid antidepressant actions. Psychopharmacology (Berl). 2022;239:1823–38.

    PubMed  CAS  Google Scholar 

  118. Béïque J-C, Imad M, Mladenovic L, Gingrich JA, Andrade R. Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci USA. 2007;104:9870–5.

    PubMed  PubMed Central  Google Scholar 

  119. Andrade R. Serotonergic regulation of neuronal excitability in the prefrontal cortex. Neuropharmacology. 2011;61:382–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  120. Muschamp JW, Regina MJ, Hull EM, Winter JC, Rabin RA. Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res. 2004;1023:134–40.

    PubMed  CAS  Google Scholar 

  121. Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 2020;21:611–24.

    PubMed  CAS  Google Scholar 

  122. Aghajanian GK, Marek GJ. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res. 1999;825:161–71.

    PubMed  CAS  Google Scholar 

  123. Baki L, Fribourg M, Younkin J, Eltit JM, Moreno JL, Park G, et al. Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells. Pflüg Arch - Eur J Physiol. 2016;468:775–93.

    CAS  Google Scholar 

  124. Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, et al. Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs. Cell. 2011;147:1011–23.

    PubMed  PubMed Central  CAS  Google Scholar 

  125. Moreno JL, Miranda-Azpiazu P, García-Bea A, Younkin J, Cui M, Kozlenkov A, et al. Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal. 2016;9:ra5–ra5.

    PubMed  PubMed Central  Google Scholar 

  126. Olivero G, Grilli M, Vergassola M, Bonfiglio T, Padolecchia C, Garrone B, et al. 5-HT2A-mGlu2/3 receptor complex in rat spinal cord glutamatergic nerve endings: A 5-HT2A to mGlu2/3 signalling to amplify presynaptic mechanism of auto-control of glutamate exocytosis. Neuropharmacology. 2018;133:429–39.

    PubMed  CAS  Google Scholar 

  127. Saha S, González-Maeso J. The crosstalk between 5-HT2AR and mGluR2 in schizophrenia. Neuropharmacology. 2023;230:109489.

    PubMed  PubMed Central  CAS  Google Scholar 

  128. Saha S, Gonzalez-Maeso J Translation-independent association of mRNAs encoding protomers of the 5-HT2A-mGlu2 receptor complex in living cells. 2024:2024.06.17.599432.

  129. Taddeucci A, Olivero G, Roggeri A, Milanese C, Giorgio FPD, Grilli M, et al. Presynaptic 5-HT2A-mGlu2/3 receptor–receptor crosstalk in the prefrontal cortex: metamodulation of glutamate exocytosis. Cells. 2022;11:3035.

    PubMed  PubMed Central  CAS  Google Scholar 

  130. Jakab RL, Goldman-Rakic PS. 5-Hydroxytryptamine2A 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. 1998;95:735–40.

    PubMed  PubMed Central  CAS  Google Scholar 

  131. Miner LAH, 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  133. Gewirtz JC, Marek GJ. behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology. 2000;23:569–76.

    PubMed  CAS  Google Scholar 

  134. Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184:1299–1313.e19.

    PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular and Biophysical Life Sciences programme, Undergraduate School, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Adam J. Drewko

  2. PhD, Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Ron L. P. Habets

  3. PhD, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands

    Tibor M. Brunt

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  1. Adam J. Drewko
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  2. Ron L. P. Habets
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AD: conceptualization, visualization, writing—original draft; RH: review and editing; TB: writing—review and editing, supervision.

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Drewko, A.J., Habets, R.L.P. & Brunt, T.M. Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects. Mol Psychiatry 30, 5926–5937 (2025). https://doi.org/10.1038/s41380-025-03169-9

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