Adverse Reactions in Psychedelic Therapy: Insights from the JAMA Psychiatry 2025 Study

Overview: In this comprehensive overview, Steve Elfrink a psychedlic therapist from OmTerra and Webdelics Subject Matter Expert, delves into a recent analysis from studies of classic psychedelics—LSD, psilocybin, and DMT—highlighting adverse reactions and an innovative hypothesis concerning trauma-related dissociative effects, termed Psychedelic Iatrogenic Structural Dissociation (PISD).

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Introduction

Psychedelics such as LSD, psilocybin, and dimethyltryptamine (DMT) are increasingly studied for their therapeutic potential in treating mental health conditions. Research highlights their generally favorable safety profile in controlled clinical settings but underscores the need for improved monitoring of adverse events (AEs). A recent hypothesis on Psychedelic Iatrogenic Structural Dissociation (PISD) explores how psychedelics may interact with trauma-related dissociative processes (Elfrink & Bergin, 2025). Below is an in-depth analysis.

Safety and Monitoring in Psychedelic Research

A systematic review and meta-analysis published in JAMA Psychiatry analyzed data from 114 studies involving 3,504 participants to assess the safety of classic psychedelics like LSD, psilocybin, DMT, and 5-MeO-DMT. The findings revealed that serious adverse events (SAEs), such as psychosis or suicidal behavior, were rare in healthy participants. Non-serious adverse events (NSAEs), including paranoia and headaches, were also uncommon. Among individuals with preexisting neuropsychiatric disorders, approximately 4% experienced SAEs, but no SAEs were reported among healthy participants (Bershad et al., 2025).

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However, researchers identified significant gaps in adverse event reporting across studies. Only 23.5% of studies systematically assessed AEs, and fewer than 30% reported all AEs rather than focusing solely on adverse drug reactions. This inconsistency raises concerns about underreporting and calls for more rigorous pharmacovigilance practices to ensure participant safety and better inform public understanding (Bershad et al., 2025).

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The controlled environments of clinical trials appear to mitigate risks compared to recreational use. For example, catastrophic outcomes such as persistent psychotic disorders or suicides have not been observed in modern trials. Standardized AE reporting aligned with FDA guidelines is critical to improving safety protocols.

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The Hypothesis of Psychedelic Iatrogenic Structural Dissociation (PISD)

Elfrink and Bergin (2025) introduced PISD, hypothesizing that psychedelics may disrupt the balance between the Apparently Normal Personality (ANP)—responsible for daily functioning—and the Emotional Personality (EP), which holds trauma-related responses. This disruption can reactivate unintegrated traumatic memories, increasing psychological destabilization in trauma-exposed individuals.

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Key Findings on PISD

• Adverse Effects: Emotional dysregulation, identity fragmentation, and derealization are observed in individuals with early trauma histories (Elfrink & Bergin, 2025).
• Neurophysiological Mechanisms: Psychedelics modulate neural patterns linked to dissociation, potentially exacerbating structural dissociation without adequate therapeutic support.
• Risk Mitigation: Trauma-informed screening protocols, preparatory assessments, and body-focused therapies are recommended to enhance safety.
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Implications for Clinical Practice

Improved Monitoring Standards

• Adopt systematic AE assessments and International Council for Harmonisation (ICH) guidelines to standardize reporting.
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Trauma-Informed Approaches

• Screen for trauma histories and dissociative symptoms.
• Integrate grounding techniques and psychotherapy post-session.
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Balancing Risks and Benefits

While psychedelics show promise for depression and PTSD, rigorous protocols are essential to minimize risks.
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Conclusion

Psychedelics demonstrate a favorable safety profile in controlled settings, but inconsistent AE reporting remains a limitation. The PISD hypothesis emphasizes the interplay between psychedelics and trauma-related dissociation, advocating for trauma-informed care to optimize therapeutic outcomes.
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Scientific References

Bershad, A. K., Scheidegger, M., & Nichols, D. E. (2025). Adverse reactions during psychedelic therapy: A systematic review of clinical trials. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2822968
Elfrink, A. M., & Bergin, M. (2025). Psychedelic iatrogenic structural dissociation (PISD): A hypothesis of trauma-related risks and opportunities in psychedelic therapy. Frontiers in Psychology, 16(1528253). https://doi.org/10.3389/fpsyg.2025.1528253
Van der Hart, O., Nijenhuis, E.R.S., & Steele K. (2006). The haunted self: Structural dissociation and the treatment of chronic traumatization. W.W. Norton & Company.

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