THE PSYCHEDELIC RENAISSANCE: A SYSTEMATIC REVIEW OF PSILOCYBIN AND LSD IN THE TREATMENT OF PSYCHIATRIC DISORDERS
Abstract
The escalating global burden of mental health disorders, coupled with the stagnation of innovation in traditional monoaminergic pharmacotherapy (e.g., SSRIs), has precipitated a critical need for novel therapeutic paradigms. This article presents a comprehensive systematic review of the so-called "Psychedelic Renaissance," focusing on the clinical resurgence of classical serotonergic hallucinogens: psilocybin and Lysergic Acid Diethylamide (LSD). The review adopts an interdisciplinary structure to evaluate the efficacy, safety, and societal implications of these compounds. Firstly, the paper traces the historical evolution of psychedelics from indigenous sacramental use, through the research proliferation of the 1950s, to the prohibitive legislation of the late 20th century. Secondly, it delineates the neurobiological mechanisms of action, specifically 5-HT2A receptor agonism and the disintegration of the Default Mode Network (DMN), which correlates with the alleviation of rigid cognitive patterns in depression and anxiety. Thirdly, the review synthesizes data from contemporary clinical trials demonstrating significant therapeutic potential in Treatment-Resistant Depression (TRD), end-of-life existential distress, and substance use disorders. Unlike standard pharmacological reviews, this paper also analyzes the distinct psychotherapeutic framework ("set and setting"), integration processes, and socio-economic factors, including cost-effectiveness and access equity. The findings suggest that psychedelic-assisted therapy represents a transformative shift from chronic symptom management to rapid, episodic curative interventions, provided that regulatory and ethical challenges are adequately addressed.
References
Bogenschutz, M. P., Ross, S., Bhatt, S., Baron, T., Forcehimes, A. A., Laska, E., ... & Mennenga, S. E. (2022). Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: A randomized clinical trial. JAMA Psychiatry, 79(10), 953–962. https://doi.org/10.1001/jamapsychiatry.2022.2096
Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., ... & Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z
Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316–344. https://doi.org/10.1124/pr.118.017160
Carhart-Harris, R. L., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., ... & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. The New England Journal of Medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994
Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., ... & Nutt, D. J. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports, 7(1), 13187. https://doi.org/10.1038/s41598-017-13282-7
Carhart-Harris, R. L., Roseman, L., Haijen, E., Erritzoe, D., Watts, R., Branchi, I., & Kaelen, M. (2018). Psychedelics and the essential importance of context. Journal of Psychopharmacology, 32(7), 725–731. https://doi.org/10.1177/0269881118754710
Gable, R. S. (2004). Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction, 99(6), 686–696. https://doi.org/10.1111/j.1360-0443.2004.00744.x
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. The Journal of Nervous and Mental Disease, 202(7), 513–520. https://doi.org/10.1097/NMD.0000000000000143
George, J. R., Michaels, T. I., Sevelius, J., & Williams, M. T. (2020). The psychedelic renaissance and the limitations of a White-dominant medical framework: A call for indigenous and ethnic minority inclusion. Journal of Psychedelic Studies, 4(1), 4–15. https://doi.org/10.1556/2054.2019.015
Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., ... & Malievskaia, E. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression. The New England Journal of Medicine, 387(18), 1637–1648. https://doi.org/10.1056/NEJMoa2206443
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., ... & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181–1197. https://doi.org/10.1177/0269881116675513
Halpern, J. H., Lerner, A. G., & Passie, T. (2016). A review of hallucinogen persisting perception disorder (HPPD) and an exploratory study of subjects claiming symptoms of HPPD. Current Topics in Behavioral Neurosciences, 36, 333–360. https://doi.org/10.1007/7854_2016_457
Higgins, J. P., Altman, D. G., Gøtzsche, P. C., Jüni, P., Moher, D., Oxman, A. D., ... & Sterne, J. A. (2011). The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ, 343, d5928. https://doi.org/10.1136/bmj.d5928
Holze, F., Gasser, P., Müller, F., Dolder, P. C., & Liechti, M. E. (2023). Acute and sustained effects of LSD in anxiety: A randomized placebo-controlled trial. Biological Psychiatry, 93(5), 430–439. https://doi.org/10.1016/j.biopsych.2022.08.017
Insel, T. R. (2017). Digital phenotyping: Technology for a new science of behavior. JAMA, 318(13), 1215–1216. https://doi.org/10.1001/jama.2017.11295
Johansen, P. Ø., & Krebs, T. S. (2015). Psychedelics not linked to mental health problems or suicidal behavior: A population study. Journal of Psychopharmacology, 29(3), 270–279. https://doi.org/10.1177/0269881114568039
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P., & Griffiths, R. R. (2014). Pilot study of the 5-HT2A agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology, 28(11), 983–992. https://doi.org/10.1177/0269881114548296
Kaelen, M., Barrett, F. S., Roseman, L., Lorenz, R., Family, N., Bolstridge, M., ... & Carhart-Harris, R. L. (2015). LSD enhances the emotional response to music. Psychopharmacology, 232(19), 3607–3614. https://doi.org/10.1007/s00213-015-4014-y
Kettner, H., Rosas, F. E., Timmermann, C., Kärtner, L., Carhart-Harris, R. L., & Roseman, L. (2021). Psychedelic communitas: Intersubjective experience during psychedelic group sessions predicts enduring changes in psychological well-being and social connectedness. Frontiers in Pharmacology, 12, 623985. https://doi.org/10.3389/fphar.2021.623985
Krebs, T. S., & Johansen, P. Ø. (2012). Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials. Journal of Psychopharmacology, 26(7), 994–1002. https://doi.org/10.1177/0269881112439253
Liechti, M. E. (2017). Modern clinical research on LSD. Neuropsychopharmacology, 42(11), 2114–2127. https://doi.org/10.1038/npp.2017.86
Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., ... & Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022
Marks, M., & Mason, I. (2021). Psychedelic patenting: The new frontier in intellectual property and mental health. JAMA Psychiatry, 78(12), 1302–1303. https://doi.org/10.1001/jamapsychiatry.2021.2829
Marseille, E., Kahn, J. G., & Yazar-Klosinski, B. (2022). The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. PLoS ONE, 15(10), e0239997. https://doi.org/10.1371/journal.pone.0239997
Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478
Nutt, D., King, L. A., & Nichols, D. E. (2013). Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nature Reviews Neuroscience, 14(8), 577–585. https://doi.org/10.1038/nrn3530
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., ... & Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 372, n71. https://doi.org/10.1136/bmj.n71
Phelps, J. (2017). Developing guidelines and competencies for the training of psychedelic therapists. Journal of Humanistic Psychology, 57(5), 450–487. https://doi.org/10.1177/0022167817711304
Preller, K. H., Razi, A., Zeidman, P., Stämpfli, P., Friston, K. J., & Vollenweider, F. X. (2019). Effective connectivity changes in LSD-induced altered states of consciousness in humans. Proceedings of the National Academy of Sciences, 116(7), 2743–2748. https://doi.org/10.1073/pnas.1815129116
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., ... & Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163(11), 1905–1917. https://doi.org/10.1176/ajp.2006.163.11.1905
Sekula, A., Gupta, I., & Prasad, P. (2022). Virtual reality as a moderator of psychedelic-assisted psychotherapy. Frontiers in Psychology, 13, 813746. https://doi.org/10.3389/fpsyg.2022.813746
Smith, W. R., & Appelbaum, P. S. (2022). Novel ethical and policy issues in psychiatric uses of psychedelic substances. Neuropharmacology, 216, 109165. https://doi.org/10.1016/j.neuropharm.2022.109165
Szigeti, B., Kartner, L., Blemings, A., Rosas, F., Feilding, A., Nutt, D. J., ... & Erritzoe, D. (2021). Self-blinding citizen science to explore psychedelic microdosing. eLife, 10, e62878. https://doi.org/10.7554/eLife.62878
Vollenweider, F. X., & Preller, K. H. (2020). Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience, 21(11), 611–624. https://doi.org/10.1038/s41583-020-0367-2
Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., ... & Roth, B. L. (2017). Crystal structure of an LSD-bound human serotonin receptor. Cell, 168(3), 377–389. https://doi.org/10.1016/j.cell.2016.12.033
Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart-Harris, R. (2017). Patients’ accounts of increased "connectedness" and acceptance after psilocybin for treatment-resistant depression. Journal of Humanistic Psychology, 57(5), 520–564. https://doi.org/10.1177/0022167817709585
World Health Organization. (2023, March 31). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression
Copyright (c) 2026 Jakub Klepacz, Radosław Swędrak, Marzena Swojnóg, Zuzanna Dobrakowska
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
