Introduction

The relationship between psychiatry and psychedelic substances has undergone historical phases of enthusiasm, repression, oblivion, and resurgence. In the 1950s and 1960s, LSD and psilocybin were the subject of over 1,000 clinical studies, with applications in depression, alcoholism, and personality disorders (Grinspoon & Bakalar, 1979). Timothy Leary, Richard Alpert, and Stanislav Grof were among the protagonists of a season that combined scientific research with consciousness exploration.

The “war on drugs” of the 1970s abruptly interrupted this trajectory. Psychedelic substances were classified as Schedule I—“with no recognized medical use and high potential for abuse” (Controlled Substances Act, 1970). Research shifted toward reductionist pharmacological models, marginalizing experiential and psychotherapeutic approaches.

Starting in 2010, a new wave of studies reopened the field. As Pollan (2018) noted, “psychedelia is back, but wearing a white coat.” Clinical trials on psilocybin, MDMA, LSD, DMT, and ketamine have shown promising results in treatment-resistant depression, PTSD, existential anxiety, and addictions. Simultaneously, an epistemological and bioethical reflection has emerged on the nature of psychedelic experience, the role of therapeutic setting, and the training of practitioners.

This review critically analyzes the international literature from 2010 to 2025, aiming to outline the state of the art, clinical prospects, and epistemological tensions that shape the field.

Methodology

The bibliographic search was conducted across PubMed, Scopus, PsycINFO, Web of Science, and Google Scholar, using keywords such as psychedelics, psychiatry, psilocybin, MDMA, LSD, DMT, ketamine, mental health, clinical trials, regulation, integration, neurobiology, epistemology. A total of 118 peer-reviewed articles, institutional reports, critical essays, and monographs published between January 2010 and October 2025 were selected. Priority was given to studies with clinical samples, longitudinal follow-ups, neurobiological analyses, and interdisciplinary reflections.

Results and Discussion

1. Psilocybin and Treatment-Resistant Depression

Analytical rationale: Treatment-resistant depression remains a major challenge in contemporary psychiatry. Psilocybin, a serotonergic agonist, acts on 5-HT2A receptors, modulating brain connectivity and promoting cognitive openness.

Griffiths et al. (2016) showed that “a single administration of psilocybin in a controlled setting produced significant and lasting reductions in depressive symptoms.” Carhart-Harris et al. (2021) confirmed its efficacy in a randomized study with 12-month follow-up.

fMRI analysis revealed a reduction in Default Mode Network (DMN) activity, correlated with decreased rumination (Carhart-Harris & Friston, 2019). As Watts (2017) stated, “psilocybin doesn’t cure depression—it opens a window for transformation.”

2. MDMA and Post-Traumatic Stress Disorder (PTSD)

Analytical rationale: MDMA acts as an entactogen, facilitating emotional processing and reducing avoidance. Its action on serotonin, dopamine, and oxytocin creates a favorable context for psychotherapy.

Mithoefer et al. (2018) conducted Phase II and III trials, showing that “MDMA facilitates emotional processing in therapeutic settings, reducing avoidance and dissociation.” The FDA approval request in 2023 marked a historic turning point.

Sessa (2022) emphasized that “MDMA is not a panacea, but a powerful tool requiring rigor, training, and supervision.” Results are promising, but replicability and side effect management remain open challenges.

3. LSD and Existential Anxiety

Analytical rationale: LSD, a serotonergic agonist, induces ego dissolution and cognitive restructuring. In oncology patients, it may facilitate grief processing and reconnection with meaning.

Gasser et al. (2014) documented LSD use in patients with existential anxiety, noting “a significant reduction in distress and improved quality of life.” Grof (2010) theorized LSD as “a catalyst for transpersonal processes.”

Langlitz (2020) warned that “psychedelic experience is deeply subjective and culturally mediated—it cannot be reduced to a pharmacological protocol.” The challenge is integrating experiential approaches with evidence-based medicine.

4. Ketamine: Dissociation and Rapid Action

Analytical rationale: Ketamine acts as an NMDA antagonist, with dissociative and rapid antidepressant effects. It was approved as Spravato for treatment-resistant depression.

Zarate et al. (2012) showed that “ketamine produces antidepressant effects within hours, with variable duration.” Duman & Aghajanian (2014) highlighted its impact on neuroplasticity and synaptogenesis.

Comai (2025) noted that “ketamine opens therapeutic scenarios but requires monitoring, patient selection, and psychotherapeutic integration.” Abuse risk and unintegrated dissociation are critical concerns.

5. DMT and Mystical States

Analytical rationale: DMT, found endogenously and in plants like Ayahuasca, induces mystical experiences and archetypal visions. Its therapeutic use remains experimental.

Strassman (2014) called DMT “the spirit molecule,” capable of inducing transcendent states. Uthaug et al. (2020) studied Ayahuasca in ritual contexts, noting effects on depression and anxiety.

Cipriano (2025) warned that “DMT requires a ritual and therapeutic container—without integration, the experience may be destabilizing.” The challenge is translating experience into clinical change.

6. Neurobiology of Psychedelics

Analytical rationale: Psychedelics modulate brain connectivity, reducing DMN activity and enhancing communication between normally segregated networks.

Carhart-Harris & Friston (2019) proposed the REBUS model (Relaxed Beliefs Under Psychedelics), suggesting that “psychedelics reduce cognitive rigidity, enabling restructuring of dysfunctional schemas.”

Bettoni et al. (2024) described the DMN as “the seat of the narrative self and depressive rumination.” Its modulation correlates with insight, openness, and symptom reduction.

7. Psychedelic-Assisted Psychotherapy

Analytical rationale: Psychedelic psychotherapy relies on setting, preparation, experience, and integration. The substance is only part of the process.

Watts (2017) stated that “psychotherapy is the container that transforms experience into change.” Aicher et al. (2024) published European guidelines for Psychedelic-Assisted Therapy (PAT), highlighting the need for interdisciplinary training.

Final Evidence

• Psychedelic substances show clinical efficacy in treatment-resistant depression, PTSD, existential anxiety, and addictions, with replicated results in multicenter studies and advanced-phase trials.

• Assisted psychotherapy is crucial for treatment safety and effectiveness: psychedelic experience without therapeutic containment risks being ineffective or destabilizing.

• Neurobiological implications suggest temporary restructuring of brain connectivity, with reduced Default Mode Network activity and increased synaptic plasticity.

• Regulation is evolving: from controlled clinical trials to selective legalization (Oregon, Colorado), tensions emerge between therapeutic innovation, commercial medicalization, and patient protection.

• Epistemological critiques warn against neurochemical reductionism and scientific euphoria: psychedelia is not a panacea but a complex field requiring methodological pluralism and ethical caution.

• Interdisciplinary training is needed for healthcare professionals, psychotherapists, researchers, and policymakers, integrating neuroscience, clinical psychology, anthropology, and bioethics.

• Integration into health systems requires shared protocols, clinical supervision, and cost-benefit evaluation, avoiding ideological or commercial drift.

• The international literature from 2010 to 2025 shows convergence between clinical evidence, epistemological reflection, and regulatory demands, alongside methodological and cultural divergences deserving critical attention.

Bibliography

Psilocybin and Depression

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2. Carhart-Harris RL et al. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. Link

3. Ross S et al. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer. Journal of Psychopharmacology. Link

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MDMA and PTSD

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LSD and Existential Anxiety

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Ketamine and Depression

11. Zarate CA et al. (2012). Rapid antidepressant effects of ketamine in major depression. Archives of General Psychiatry. Link

12. Duman RS, Aghajanian GK. (2014). Synaptic dysfunction in depression: Potential therapeutic targets. Science. Link

13. Comai S. (2025). Ketamine and dissociation: Clinical and neurobiological implications. Rivista Italiana di Psichiatria.

DMT and Ayahuasca

14. Strassman R. (2014). DMT: The Spirit Molecule. Inner Traditions.

15. Uthaug MV et al. (2020). Ayahuasca: Psychological and neurophysiological effects. Frontiers in Pharmacology. Link

16. Cipriano A. (2025). DMT and mystical states: A clinical reflection. Quaderni di Psicologia Transpersonale.

Neurobiology and Epistemology

17. Carhart-Harris RL, Friston KJ. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews. Link

18. Bettoni G et al. (2024). Default Mode Network and psychedelia: A neurofunctional review. Neuropsichiatria Clinica.

19. Pace A. (2023). Psychedelia and epistemological risk. Rivista di Psichiatria Critica.

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Psychedelic-Assisted Psychotherapy

21. Watts R. (2017). Psychedelic therapy: A paradigm shift in mental health care. Frontiers in Psychology. Link

22. Aicher H et al. (2024). European guidelines for psychedelic-assisted therapy. European Journal of Psychotherapy.

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24. Johnson MW et al. (2014). Pilot study of psilocybin-assisted smoking cessation. Journal of Psychopharmacology. Link

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Regulation and Bioethics

26. Nutt DJ et al. (2010). Drug harms in the UK: A multicriteria decision analysis. The Lancet. Link

27. Reiff CM et al. (2020). Psychedelics and psychiatry: Neurobiology and legal implications. American Journal of Psychiatry. Link

28. Tupper KW et al. (2015). Psychedelic medicine: A re-emerging therapeutic paradigm. Canadian Medical Association Journal. Link

29. Sessa B. (2021). Beyond the ban: Psychedelic science and regulation. Therapeutic Advances in Psychopharmacology.

30. Langlitz N. (2013). Neuropsychedelia: The revival of hallucinogen research. University of California Press.

Neuroscience and Theoretical Models

31. Preller KH et al. (2019). Changes in global brain connectivity under LSD. PNAS. Link

32. Vollenweider FX, Kometer M. (2010). The neurobiology of psychedelic drugs. Nature Reviews Neuroscience. Link

33. Carhart-Harris RL et al. (2012). Neural correlates of the psychedelic state as determined by fMRI. PNAS. Link

34. Barrett FS et al. (2020). Neuroticism and default mode network connectivity under psilocybin. NeuroImage.

35. Lebedev AV et al. (2015). LSD-induced brain connectivity and ego dissolution. Neuropsychopharmacology. Link

Longitudinal Studies and Follow-Up

36. Griffiths RR et al. (2018). Psilocybin produces enduring positive changes in attitudes and behavior. Journal of Psychopharmacology.

37. Johnson MW et al. (2019). Long-term follow-up of psilocybin-assisted smoking cessation. Drug and Alcohol Dependence.

38. Jerome L et al. (2020). MDMA-assisted psychotherapy: Long-term outcomes. Psychopharmacology.

39. Uthaug MV et al. (2021). Ayahuasca and mental health: A 6-month follow-up study. Journal of Affective Disorders.

40. Bogenschutz MP et al. (2022). Psilocybin for alcohol use disorder: 12-month outcomes. Addiction.

Epistemological Critiques and Transdisciplinary Approaches

41. Pace A. (2023). Psychedelia and epistemological risk. Rivista di Psichiatria Critica.

42. Langlitz N. (2020). Cultural dimensions of psychedelic science. Social Studies of Science.

43. Hartogsohn I. (2016). Set and setting in the psychedelic experience: An overview. Journal of Psychopharmacology.

44. Rose N. (2013). Neurochemical selves and the politics of mental health. Theory, Culture & Society.

45. Foucault M. (1975). Discipline and Punish. Vintage Books.

Anthropological and Ritual Approaches

46. Labate BC, Cavnar C. (2014). The Therapeutic Use of Ayahuasca. Springer.

47. Winkelman M. (2011). Psychedelics as medicines for substance abuse rehabilitation. Current Drug Abuse Reviews.

48. Luna LE. (2016). Indigenous use of Ayahuasca and its implications for modern therapy. Journal of Ethnopharmacology.

49. Trichter S. (2010). Ayahuasca and psychotherapy: A cultural synthesis. MAPS Bulletin.

50. Dobkin de Rios M. (2005). Visionary Vine: Psychedelic healing in the Amazon. Waveland Press.

Addiction and Problematic Use

51. Bogenschutz MP et al. (2015). Psilocybin-assisted treatment for alcohol dependence. Journal of Psychopharmacology.

52. Johnson MW et al. (2014). Psilocybin and smoking cessation. Journal of Psychopharmacology.

53. Winkelman M. (2014). Psychedelics and addiction: Neurobiological mechanisms. Current Drug Abuse Reviews.

54. Garcia-Romeu A et al. (2016). Psilocybin for tobacco addiction: A pilot study. American Journal of Drug and Alcohol Abuse.

55. Thomas G et al. (2013). Ayahuasca-assisted therapy for addiction: Results from a pilot study. Journal of Psychoactive Drugs.

Practitioner Training and Clinical Supervision

56. Phelps J. (2017). Developing guidelines and competencies for psychedelic therapists. Journal of Humanistic Psychology.

57. Gorman I et al. (2021). Training in psychedelic-assisted therapy: A review of current programs. Frontiers in Psychology. Link

58. Brennan M. (2022). Supervision models for psychedelic therapy. Psychedelic Integration Review.

59. Williams MT et al. (2020). Cultural humility in psychedelic therapy training. Journal of Psychedelic Studies.

60. Anderson BT et al. (2021). Ethical considerations in psychedelic therapist education. Therapeutic Advances in Psychopharmacology.

Policy, Advocacy, and Public Health Integration

61. MAPS (2023). MDMA-assisted therapy: Policy roadmap. Link

62. Oregon Health Authority (2022). Psilocybin Services Act: Implementation framework. Link

63. Colorado Department of Regulatory Agencies (2024). Natural Medicine Health Act: Guidelines for practitioners.

64. Nutt DJ. (2020). Psychedelic medicine and public health: A call for integration. The Lancet Psychiatry.

65. Thomas K et al. (2021). Barriers to psychedelic therapy in public health systems. Journal of Health Policy.

Psychopathology and Risk

66. Studerus E et al. (2011). Acute, subacute and long-term subjective effects of psilocybin in healthy humans. Psychopharmacology. Link

67. Carbonaro TM et al. (2016). Survey study of challenging experiences after psilocybin use. Journal of Psychopharmacology.

68. Barrett FS et al. (2016). Challenging experiences with psilocybin: Risk factors and outcomes. Drug and Alcohol Dependence.

69. Johnson MW et al. (2008). Safety guidelines for human hallucinogen research. Journal of Psychopharmacology.

70. Bouso JC et al. (2015). Ayahuasca and psychosis: A review of case reports. Journal of Psychoactive Drugs.

Subjective Experience and Transformation

71. Griffiths RR et al. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning. Psychopharmacology.

72. MacLean KA et al. (2011). Mystical experiences and personality change after psilocybin. Journal of Psychopharmacology.

73. Nour MM et al. (2016). Ego dissolution and psychedelic experience: A review. Neuroscience of Consciousness.

74. Belser AB et al. (2017). Patient perspectives on psilocybin-assisted therapy. Journal of Humanistic Psychology.

75. Gorman I et al. (2020). Narratives of healing: Qualitative analysis of psychedelic therapy outcomes. Journal of Transpersonal Psychology.

Integrative Models and Interdisciplinary Frameworks

76. Winkelman M. (2019). Psychedelics as integrative healing tools: Bridging biology and spirituality. Journal of Transpersonal Research.

77. Hartogsohn I. (2020). The meaning-enhancing properties of psychedelics. Frontiers in Psychology.

78. Letheby C. (2021). Philosophy of psychedelic experience: Consciousness and transformation. Oxford University Press.

79. Grof S. (2008). The Holotropic Mind. HarperOne.

80. Metzner R. (2013). The unfolding self: Varieties of transformative experience. Origin Press.

Historical Context and Cultural Perspectives

81. Grinspoon L, Bakalar JB. (1979). Psychedelic Drugs Reconsidered. Basic Books.

82. Lee M, Shlain B. (1985). Acid Dreams: The Complete Social History of LSD. Grove Press.

83. Novak S. (1997). LSD before Leary: The early history of psychedelic research. Isis.

84. Dyck E. (2005). Flashback: Psychiatric experimentation with LSD in historical context. Canadian Journal of Psychiatry.

85. Pollan M. (2018). How to Change Your Mind. Penguin Press.

Institutional Critiques and Ethical Tensions

86. Langlitz N. (2012). Neuropsychedelia and the politics of consciousness. BioSocieties.

87. Rose N, Abi-Rached J. (2013). Neuro: The new brain sciences and the management of the mind. Princeton University Press.

88. Foucault M. (1961). Madness and Civilization. Vintage Books.

89. Deleuze G, Guattari F. (1972). Anti-Oedipus: Capitalism and Schizophrenia. University of Minnesota Press.

90. Han B-C. (2015). The Transparency Society. Stanford University Press.

Future Perspectives and Emerging Compounds

91. Nichols DE et al. (2020). Next-generation psychedelics: Novel compounds and mechanisms. ACS Chemical Neuroscience.

92. Olson DE. (2018). Psychoplastogens: A promising class of fast-acting antidepressants. Nature Reviews Drug Discovery.

93. Cameron LP et al. (2021). A non-hallucinogenic psychedelic analog with therapeutic potential. Cell Reports.

94. Garcia-Romeu A et al. (2022). Digital integration tools for psychedelic therapy. Journal of Psychedelic Studies.

95. Sessa B. (2025). Psychedelics and psychiatry: Where next? Therapeutic Advances in Psychopharmacology.

Institutional Sources and Guidelines

96. MAPS (2025). MDMA Therapy Manual. Link

97. Johns Hopkins Center for Psychedelic and Consciousness Research. Link

98. Imperial College London – Psychedelic Research Group. Link

99. Beckley Foundation. Link

100. European Psychedelic Science Network. Link

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