Trauma-informed Psilocybin Assisted Psychotherapy (TiPAP) for PTSD

Early Phase 1RecruitingNCT07737054

Tel-Aviv Sourasky Medical Center13 enrolled

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.

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

Psilocybin (drug)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 prepared through preparatory psychotherapy sessions and remain in the clinic during the acute drug effects. Each session lasts approximately six hours, after which participants are discharged following physician evaluation. Integration psychotherapy sessions follow each dosing session. After each dosing session, participants are accompanied home by a designated escort or transported by taxi to their care. The first integration psychotherapy session is held the following morning.

Trauma-Focused PsychotherapyBEHAVIORAL

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 three integration sessions following each dosing session (six in total). Preparation focuses on therapeutic alliance and readiness for the psychedelic experience. Integration sessions support trauma processing, meaning-making, and incorporation of insights into daily functioning. The approach emphasizes flexible re-engagement with trauma-related memories while fostering a broader and more adaptive sense of self.

Eligibility

Sex: ALLMin age: 21 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Number of Participants With One or More Treatment-Emergent Adverse Events

Treatment-emergent adverse events (TEAEs) are defined as any medical or psychological adverse event that begins or worsens after the first psilocybin administration. The reported outcome will be the number of participants experiencing at least one TEAE from the first dosing session through the 30-day follow-up period. Treatment-emergent adverse events (TEAEs) will be identified through clinical assessments conducted by the study physician and psychologist, monitoring of vital signs (blood pressure and heart rate), participant self-reports, administration of the Columbia-Suicide Severity Rating Scale (C-SSRS) to assess suicidal ideation and behavior, and the Swiss Psychedelic Side Effects Inventory (SPSI) to systematically assess psychedelic-related side effects. Serious adverse events (SAEs) will be monitored, documented, and reported in accordance with the study safety reporting procedures.

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

Feasibility and tolerability will be assessed by the number of participants who successfully complete the full therapeutic intervention, defined as completion of both psilocybin administration sessions and all protocol-required preparatory and integration psychotherapy sessions. Successful completion of the intervention reflects the feasibility of implementing the study protocol as planned and the tolerability of the intervention.

Time frame: From enrollment through completion of the 30-day follow-up assessment.

Secondary Outcomes

Change in PTSD Symptom Severity as Measured by CAPS-5

PTSD symptom severity will be assessed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The outcome measure will reflect the change in CAPS-5 total score from baseline to 30 days after completion of the therapeutic intervention.

Time frame: Baseline to 30 days after completion of the therapeutic intervention