Have a personal or library account? Click to login
Exploring the Therapeutic Potential of Psilocybin and Ketamine in Major Depressive Disorder including Treatment-Resistant Depression: A Narrative Review Cover

Exploring the Therapeutic Potential of Psilocybin and Ketamine in Major Depressive Disorder including Treatment-Resistant Depression: A Narrative Review

Open Access
|Jul 2025

References

  1. Maldonado-García JL, García-Mena LH, Mendieta-Cabrera D, Pérez-Sánchez G, Becerril-Villanueva E, Alvarez-Herrera S, et al. Use of Extracellular Monomeric Ubiquitin as a Therapeutic Option for Major Depressive Disorder. Pharmaceuticals. 2024 Jun 27;17(7):841.
  2. Kim KY, Shin KY, Chang KA. Potential Inflammatory Biomarkers for Major Depressive Disorder Related to Suicidal Behaviors: A Systematic Review. Int J Mol Sci. 2023 Sep 9;24(18):13907.
  3. Gong X, Chang R, Zou J, Tan S, Huang Z. The role and mechanism of tryptophan - kynurenine metabolic pathway in depression. Rev Neurosci. 2023 Apr 25;34(3):313–24.
  4. Obuobi-Donkor G, Nkire N, Agyapong VIO. Prevalence of Major Depressive Disorder and Correlates of Thoughts of Death, Suicidal Behaviour, and Death by Suicide in the Geriatric Population—A General Review of Literature. Behav Sci. 2021 Oct 21;11(11):142.
  5. Veluri N, Mansuri Z. How effective are ketamine or esketamine in treatment-resistant depression? Eur Psychiatry. 2021 Aug 13;64(Suppl 1):S330.
  6. Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv Wash DC. 2014 Aug 1;65(8):977–87.
  7. Ivanets NN, Svistunov AA, Chubarev VN, Kinkulkina MA, Tikhonova YG, Syzrantsev NS, et al. Can Molecular Biology Propose Reliable Biomarkers for Diagnosing Major Depression? Curr Pharm Des. 2021;27(2):305–18.
  8. Remmers MCC, Reijs RP, Hoebe CJPA. Defining and distinguishing early life stress, trauma, adversity, toxic and chronic stress and allostatic load: a descriptive review. Scand J Public Health. 2024 Aug 1;14034948241260105.
  9. Khalifa MA, Salaheldin AO, Elsead JA, Aboud FA, Korim BM, Abdalsttar SS, et al. Assessing the Impact of Gepirone on Major Depressive Disorder ‐ A systematic review and meta analysis. Alzheimers Dement. 2025 Jan 9;20(Suppl 8):e095197.
  10. van Hees MLJM, Rotter T, Ellermann T, Evers SMAA. The effectiveness of individual interpersonal psychotherapy as a treatment for major depressive disorder in adult outpatients: a systematic review. BMC Psychiatry. 2013 Jan 11;13:22.
  11. Pappa *Sofia, Shah M, Young S, Anwar T, Ming T. CLINICAL AND ECONOMIC BURDEN OF MAJOR AND TREATMENT-RESISTANT DEPRESSION IN A POPULATION-BASED STUDY COHORT OF 110.000 PATIENTS. Int J Neuropsychopharmacol. 2025 Feb 12;28(Suppl 1):i20.
  12. Di Salvo G, Perotti C, Ricci V, Maina G, Rosso G. Efficacy and suitability of adding short-term psychodynamic psychotherapy (STPP) to pharmacotherapy in patients with depressive disorders: a systematic review. Trends Psychiatry Psychother. 2024 Apr 30;
  13. Schlaepfer TE, Agren H, Monteleone P, Gasto C, Pitchot W, Rouillon F, et al. The hidden third: improving outcome in treatment-resistant depression. J Psychopharmacol Oxf Engl. 2012 May;26(5):587–602.
  14. Youssef NA, McCall WV. Relapse prevention after index electroconvulsive therapy in treatment-resistant depression. Ann Clin Psychiatry Off J Am Acad Clin Psychiatr. 2014 Nov;26(4):288–96.
  15. Torres S. Psychedelics: A new era of treatment? Eur Psychiatry. 2021 Aug 13;64(Suppl 1):S483.
  16. Bright S, Williams M, Caldicott D. Should addiction researchers be interested in psychedelic science? Drug Alcohol Rev. 2017 May;36(3):285–7.
  17. Forstmann M, Sagioglou C. New Insights Into the Clinical and Nonclinical Effects of Psychedelic Substances: An Integrative Review. Eur Psychol. 2022 Oct;27(4):291–301.
  18. Stewart LH. The dissociative psychedelic renaissance. J Psychedelic Stud. 2018 Dec;2(2):61–3.
  19. Bartoli F, Cavaleri D, Riboldi I, Crocamo C, de Filippis R, Zandonella Callegher R, et al. The Resistant Depression Response to Esketamine Assessing Metabolomics (ReDREAM) Project—Untargeted Metabolomics to Identify Biomarkers of Treatment Response to Intranasal Esketamine in Individuals with Treatment-Resistant Depression: A Study Protocol. Alpha Psychiatry. 2024 Aug 1;25(4):555–60.
  20. de Filippis R, De Fazio P. Esketamine nasal spray in severe bipolar depression with borderline personality disorder and history of multiple substance abuse: A case report. Bipolar Disord. 2023 Sep;25(6):524–6.
  21. Thaoboonruang N, Lohitnavy M, Lohitnavy O. Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom (Psilocybe cubensis): A Systematic Review. J Psychoactive Drugs. 2024 Sep 10;1–13.
  22. Carhart-Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Evans J, et al. Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr Bull. 2013 Nov;39(6):1343–51.
  23. Siegel JS, Subramanian S, Perry D, Kay BP, Gordon EM, Laumann TO, et al. Psilocybin desynchronizes the human brain. Nature. 2024;632(8023):131–8.
  24. 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 Engl. 2024 May;38(5):489–99.
  25. Kinderlehrer DA. Mushrooms, Microdosing, and Mental Illness: The Effect of Psilocybin on Neurotransmitters, Neuroinflammation, and Neuroplasticity. Neuropsychiatr Dis Treat. 2025 Jan 29;21:141–55.
  26. Kritzer MD, Mischel NA, Young JR, Lai CS, Masand PS, Szabo ST, et al. Ketamine for treatment of mood disorders and suicidality: A narrative review of recent progress. Ann Clin Psychiatry Off J Am Acad Clin Psychiatr. 2022 Feb;34(1):33–43.
  27. Kang MJY, Hawken E, Vazquez GH. The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity. Front Psychiatry. 2022 Apr 25;13:860882.
  28. Kopelman J, Keller TA, Panny B, Griffo A, Degutis M, Spotts C, et al. Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. Transl Psychiatry. 2023 May 9;13:159.
  29. 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 May 1;78(5):481–9.
  30. von Rotz R, Schindowski EM, Jungwirth J, Schuldt A, Rieser NM, Zahoranszky K, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. eClinicalMedicine. 2023 Feb 1;56:101809.
  31. Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol (Oxf). 2022 Feb 1;36(2):151–8.
  32. Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study’s patient-level data with fidelity to the original research protocol. BMJ Open. 2023 Jul 25;13(7):e063095.
  33. Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul 1;3(7):619–27.
  34. Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018 Feb 1;235(2):399–408.
  35. 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 Nov 2;387(18):1637–48.
  36. 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 Apr 14;384(15):1402–11.
  37. 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 Sep;48(10):1492–9.
  38. Ionescu DF, Fu DJ, Qiu X, Lane R, Lim P, Kasper S, et al. Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neu-ropsychopharmacol. 2021 Jan 1;24(1):22–31.
  39. Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019 Sep 1;76(9):893.
  40. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616–30.
  41. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428–38.
  42. Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju O, Swee MB, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. J Affect Disord. 2019 Jan;243:516–24.
  43. Ohtani Y, Tani H, Nomoto-Takahashi K, Yatomi T, Yonezawa K, Tomiyama S, et al. Efficacy and safety of intravenous ketamine treatment in Japanese patients with treatment-resistant depression: A double-blind, randomized, placebo-controlled trial. Psychiatry Clin Neurosci. 2024 Dec;78(12):765–75.
  44. Pattanaseri K, Lortrakul J, Jaisin K, Srifuengfung M, Sa-Nguanpanich N, Viravan N, et al. A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression. BMC Psychiatry. 2024 Jul 18;24(1):512.
  45. Zolghadriha A, Anjomshoaa A, Jamshidi MR, Taherkhani F. Rapid and sustained antidepressant effects of intravenous ketamine in treatment-resistant major depressive disorder and suicidal ideation: a randomized clinical trial. BMC Psychiatry. 2024 May 7;24(1):341.
  46. Loo C, Glozier N, Barton D, Baune BT, Mills NT, Fitzgerald P, et al. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Br J Psychiatry J Ment Sci. 2023 Dec;223(6):533–41.
  47. Glue P, Loo C, Fam J, Lane HY, Young AH, Surman P, et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nat Med. 2024 Jul;30(7):2004–9.
  48. Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Morrison RL, et al. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression— TRANSFORM-3. Am J Geriatr Psychiatry. 2020 Feb;28(2):121–41.
  49. Knochel C, Alves G, Friedrichs B, Schneider B, Schmidt-Rechau A, Wenzler S, et al. Treatment-resistant Late-life Depression: Challenges and Perspectives. Curr Neuropharmacol. 2015 Oct 13;13(5):577–91.
  50. van Elk M, Fried EI. History repeating: guidelines to address common problems in psychedelic science. Ther Adv Psychopharmacol. 2023 Jan 1;13:20451253231198466.
  51. Sessa B. The Psychedelic Renaissance: Reassessing the Role of Psychedelic Drugs in 21st Century Psychiatry and Society: Second Edition. Aeon Books; 2020. 402 p.
DOI: https://doi.org/10.2478/bgbl-2025-0011 | Journal eISSN: 2956-6851 | Journal ISSN: 0373-174X
Language: English
Page range: 147 - 166
Accepted on: Jun 16, 2025
Published on: Jul 2, 2025
Published by: The Medical Library named after S. Konopka in Warsaw
In partnership with: Paradigm Publishing Services
Publication frequency: 2 issues per year

© 2025 Christian S. Skowron, Urszula Miłkowska, Gabriela Maria Piech, Igor Lis, Piotr Kurzyna, published by The Medical Library named after S. Konopka in Warsaw
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.