Psilocybin-Assisted Psychotherapy for Veterans With PTSD

Psilocybin-Assisted Psychotherapy for Posttraumatic Stress Disorder in Military Veterans: A Pilot Feasibility Study

This study will evaluate the feasibility, safety and preliminary efficacy of psilocybin-assisted psychotherapy in military veterans with treatment-refractory posttraumatic stress disorder (PTSD).

Posttraumatic stress disorder (PTSD) is a severe and debilitating mental health condition that significantly impacts patients' lives, leading to functional impairments, strained relationships, and high healthcare costs. About half of the patients with PTSD do not benefit from current evidence-based psychotherapy and available pharmacological treatments offer only limited benefits. Therefore, there is a high need for novel therapeutic approaches in the treatment of PTSD.

Psilocybin-assisted psychotherapy is a promising approach combining the pharmacological effects of psilocybin, a serotonergic psychedelic, with psychotherapy. Psilocybin-assisted psychotherapy has shown promising effects in several phase 2 studies in the treatment of mental health conditions such as depression and end-of-life anxiety, with two phase 3 studies underway for treatment-resistant depression. Building on these initial promising results, psilocybin-assisted psychotherapy is increasingly being studied for other psychiatric indications, including PTSD.

Many of psilocybin's potential therapeutic mechanisms appear to be transdiagnostic in nature. For example, studies suggest that psilocybin can enhance introspection, emotional processing, and psychological flexibility, all of which could facilitate psychotherapeutic processes. Psilocybin has also been shown to reduce avoidance and promote neural plasticity and cognitive reappraisal, which could be particularly relevant for addressing core symptoms of PTSD, such as persistent avoidance and rigid negative thought patterns. Furthermore, its ability to foster a sense of connectedness aligns well with the therapeutic need of individuals with PTSD who face challenges related to social isolation.

Preliminary findings from an initial Phase 2 trial suggest that psilocybin-assisted psychotherapy may be safe and associated with clinically meaningful improvements in PTSD symptoms. However, this study differed from the present study in several important aspects. Participants were not required to have had previous unsuccessful evidence-based psychotherapies for PTSD, and psilocybin administration was not embedded within psychotherapeutic treatment. The current open-label pilot study will focus on veterans with treatment-refractory PTSD, a patient population that frequently shows partial or no response to standard evidence-based PTSD treatment. In addition, psilocybin administration will be part of an extensive psychotherapeutic treatment protocol. This study aims to collect data on the feasibility, preliminary efficacy and safety of psilocybin-assisted psychotherapy in this population, to inform a potential future randomized controlled trial.

Inclusion Criteria:

• Are between 18 and 70 years old.
• Able to provide written informed consent.
• Fluent in speaking and reading Dutch.
• Is a veteran of the Dutch Armed Forces.
• Able to swallow pills.
• Have a body mass index (kg/m2) of >18.0.
• Meet DSM-5 criteria for current PTSD.
• Meet criteria for treatment-refractory PTSD.
• Agree to have study visits audiovisually recorded.
• Able to provide a contact (relative, spouse, close friend, or other support person) who is willing and able to be reached by the investigators in the event of the participant becoming unwell or unreachable.

Exclusion Criteria:

• Has a history of any medical condition that could make receiving psilocybin harmful because of temporary increases in blood pressure and heart rate.
• Has a medical or psychiatric condition that could interfere with study participation or pose a risk to the participant's safety or well-being.
• Has uncontrolled hypertension.
• Unable or unwilling to safely taper-off prohibited psychiatric medication.
• Has been exposed to electroconvulsive therapy (ECT) within 12 weeks of enrollment.
• Has any current problem which, in the opinion of the investigator, might interfere with study participation.