Trauma-informed Psilocybin Assisted Psychotherapy (TiPAP) for PTSD

Official title

Trauma-informed Psilocybin Assisted Psychotherapy (TiPAP) for Post-Traumatic Stress Disorder

Overview

This is an open-label pilot study designed to evaluate the safety, tolerability, and preliminary clinical effects of psilocybin-enhanced trauma-focused psychotherapy in individuals with post-traumatic stress disorder (PTSD). Participants will receive a structured therapeutic protocol that includes preparatory sessions, two psilocybin administration sessions (15 mg followed by 25 mg), and integration sessions based on a trauma-focused therapeutic approach. The primary objective of the study is to assess the safety and tolerability of psilocybin administration in this clinical population. Secondary objectives include evaluating changes in PTSD symptom severity, as measured by the Clinician-Administered PTSD Scale (CAPS-5), at 30 days following treatment. This pilot study will include 13 participants and is intended to inform the feasibility and design of a subsequent randomized controlled trial.

Detailed description

This study is an open-label pilot clinical trial evaluating the safety, tolerability, and preliminary clinical effects of psilocybin-enhanced trauma-focused psychotherapy for the treatment of post-traumatic stress disorder (PTSD).

PTSD is a chronic and disabling condition characterized by intrusive symptoms, avoidance, negative alterations in cognition and mood, and hyperarousal. Despite the availability of evidence-based psychotherapies and pharmacological treatments, a substantial proportion of patients do not achieve sufficient symptom relief, highlighting the need for novel and rapid-acting interventions.

Psilocybin, a serotonergic psychedelic compound, has demonstrated potential therapeutic effects in a range of psychiatric conditions, including depression, anxiety, and trauma-related disorders. When administered in a controlled therapeutic setting, psilocybin may facilitate emotional processing, cognitive flexibility, and adaptive reorganization of trauma-related memories.

In this study, psilocybin administration is combined with an integrative trauma-focused psychotherapeutic framework based on principles of Acceptance and Commitment Therapy (ACT) and Narrative Exposure Therapy (NET). ACT emphasizes psychological flexibility, acceptance, self-as-context, and values-based action, supporting individuals in changing their relationship with trauma-related internal experiences. NET complements this approach by facilitating the structured integration of traumatic memories within a coherent autobiographical narrative, embedding the traumatic experience within the broader context of the individual's life story. Together, this framework is designed to support the processing of traumatic experiences within an expanded and flexible cognitive-emotional context, promoting adaptive meaning-making and reconnection with a broader sense of self.

Participants will undergo a structured treatment protocol consisting of preparatory sessions, two psilocybin administration sessions (15 mg for the first session and 25 mg for the second session), and post-session integration sessions.

The study physician retains clinical authority to discontinue a dosing session or withdraw a participant at any time, including in the event of sustained cardiovascular distress, severe psychological distress unresponsive to support, or acute psychiatric decompensation.

The primary objective of the study is to evaluate the safety and tolerability of psilocybin administration in individuals with PTSD. Safety will be assessed through monitoring of adverse events and clinical observations throughout the study.

Secondary objectives include assessing changes in PTSD symptom severity using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 30 days following the intervention.

This pilot study will enroll 13 participants and is intended to provide preliminary data on feasibility, safety, and potential clinical effects to inform the design of a future randomized controlled trial.

Interventions

• Drug Psilocybin (drug)
  Psilocybin is a naturally occurring psychedelic compound and a prodrug of psilocin, which exerts its effects primarily through serotonergic receptor activity. In this study, psilocybin is administered orally in two dosing sessions (15 mg followed by 25 mg) in a controlled clinical setting, with a minimum interval of one week between sessions. Administration is performed by a study physician, who provides medical oversight, monitors vital signs, and evaluates acute responses. Participants are pr
• Behavioral Trauma-Focused Psychotherapy
  The psychotherapy intervention is based on an integrative trauma-focused framework combining Acceptance and Commitment Therapy (ACT) and Narrative Exposure Therapy (NET). Psilocybin-assisted psychotherapy aims to facilitate emotional processing, psychological flexibility, and contextual integration of traumatic memories within a coherent autobiographical narrative. The intervention is delivered by a licensed therapist and includes two preparatory sessions, two psilocybin dosing sessions, and thr

Primary outcome measures

• Number of Participants With One or More Treatment-Emergent Adverse Events [Time frame: From the first psilocybin administration session through 30 days after completion of the therapeutic intervention.]
• Number of Participants Completing the Full Therapeutic Intervention [Time frame: From enrollment through completion of the 30-day follow-up assessment.]

Secondary outcome measures (1)

• Change in PTSD Symptom Severity as Measured by CAPS-5 [Time frame: Baseline to 30 days after completion of the therapeutic intervention]

Eligibility criteria

Inclusion criteria

• Age 21-65 years.
• Diagnosis of post-traumatic stress disorder (PTSD) according to DSM-5 criteria, as assessed by CAPS-5.
• At least 1 year since the traumatic event.
• Moderate or greater PTSD severity (CAPS-5 score ≥ 25).
• Ability to provide written informed consent.
• Ability to read, write, speak, and understand Hebrew.
• Prior trauma-focused psychotherapy.
• Medically healthy at screening, as determined by a study physician, including:

• No exclusionary medical conditions.
• Resting blood pressure between 90/60 and 150/90 mmHg and heart rate between 45-100 bpm.
• Normal laboratory results (including liver function, renal function, and electrolytes).

Exclusion criteria

• Current or past diagnosis of psychotic disorders, bipolar disorder, schizoaffective disorder, dissociative identity disorder, or borderline personality disorder (as assessed by MINI or SCID-5-SPQ).
• Current psychotic features.
• First-degree relative with a history of a psychotic disorder.
• History of antidepressant-induced mania or hypomania.
• Significant suicidal risk as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS), including active suicidal ideation with intent or plan, or suicidal behavior within the past 6 months.
• Substance use disorder (excluding nicotine and caffeine); mild-to-moderate alcohol or cannabis use may be permitted under monitoring and PI approval.
• Use of psychedelic substances within 3 months before enrollment
• Participation in a clinical trial involving administration of a psychedelic substance within the past 12 months.
• History of adverse psychological reaction to psychedelics requiring hospitalization.
• Significant cardiovascular disease, including ischemic heart disease, uncontrolled hypertension, arrhythmia, or heart failure (NYHA class ≥3).
• Dementia or suspected cognitive impairment.
• Traumatic brain injury with loss of consciousness >24 hours or post-traumatic amnesia >7 days (unless cleared by neurological evaluation).
• Pregnancy, breastfeeding, or positive pregnancy/drug test (excluding cannabis) on the day of dosing.
• BMI <18 or >33
• Abnormal liver or renal function tests.
• Use of medications contraindicated with psilocybin.
• Changes in psychiatric medication (dose or type) within one month before enrollment.
• Needle phobia or inability to undergo blood testing.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Israel · 1 center

• Tel Aviv Sourasky Medical Center — Tel Aviv

Publications

• Neisewander B, Moreau C. Trauma-Focused ACT: A Practitioner's Guide to Working With Mind, Body, and Emotion Using Acceptance and Commitment Therapy. Am J Psychother. 2024 Dec 12;77(4):215-216. doi: 10.1176/appi.psychotherapy.20240018. Epub 2024 Nov 6. No abstract available. PMID 39504448
• Mitchell JM, Ot'alora G M, van der Kolk B, Shannon S, Bogenschutz M, Gelfand Y, Paleos C, Nicholas CR, Quevedo S, Balliett B, Hamilton S, Mithoefer M, Kleiman S, Parker-Guilbert K, Tzarfaty K, Harrison C, de Boer A, Doblin R, Yazar-Klosinski B; MAPP2 Study Collaborator Group. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023 Oct;29(10) PMID 37709999
• Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MHB, Lean M, Licht RW, Maples-Kel PMID 36322843
• Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, Kalin NH, McDonald WM; the Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of Research. Psychedelics and Psychedelic-Assisted Psychotherapy. Am J Psychiatry. 2020 May 1;177(5):391-410. doi: 10.1176/appi.ajp.2019.19010035. Epub 2020 Feb 26. PMID 32098487
• Johnson MW, Griffiths RR. Potential Therapeutic Effects of Psilocybin. Neurotherapeutics. 2017 Jul;14(3):734-740. doi: 10.1007/s13311-017-0542-y. PMID 28585222
• Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials. JAMA. 2015 Aug 4;314(5):489-500. doi: 10.1001/jama.2015.8370. PMID 26241600

Identifiers

NCT: NCT07737054 · 0101-24-PILOT · Internal Study ID

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗