Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000799459
Ethics application status
Approved
Date submitted
26/06/2025
Date registered
28/07/2025
Date last updated
28/07/2025
Date data sharing statement initially provided
28/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of Fly-In-Fly-Out (FIFO) model of Psilocybin-Assisted Therapy (PAT) for Major Depressive Disorder (MDD)
Scientific title
FIFO-PAT-20: A sequential multiple assignment randomised controlled trial comparing the efficacy and safety of treatment as usual against a Fly-In-Fly-Out (FIFO) model of Psilocybin-Assisted Therapy (PAT) for Major Depressive Disorder (MDD), alongside randomised adjunctive support (virtual-reality vs journalling)
Secondary ID [1] 314559 0
Nil
Universal Trial Number (UTN)
Trial acronym
FIFO-PAT-201
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 337672 0
Condition category
Condition code
Mental Health 334007 334007 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial investigates a new treatment program for Major Depressive Disorder (MDD), using Psilocybin-Assisted Therapy (PAT). The treatment involves psychotherapy sessions, a single 25 mg oral dose of the psychedelic substance psilocybin, and a reflective integration tool (a VR headset or journal) for home use. The intervention spans approximately ten weeks.

Participants will continue working with their regular psychotherapist, who will be paired with a specialist psychedelic therapist. The treatment will be delivered at a clinical partner organisation, and not a research centre. This model of care is referred to as ‘fly-in-fly-out psychedelic-assisted therapy’ (FIFO-PAT). All psychotherapists working on the study have undergone PAT specific training, delivered by qualified PAT supervisors. There will be ongoing supervision and support provided to therapists throughout the trial.

Following a multi-stage screening procedure, the treatment for enrolled participants will typically include:

-Three 90-minute preparatory psychotherapy sessions over three weeks. These sessions are designed to build rapport between the participant and therapists and prepare the participant for the psilocybin experience by providing education on the effects of psilocybin and discussing the participants intentions.
-One dosing session (25 mg psilocybin capsule administered alongside therapeutic support). The dosing session will occur the week after the third preparatory session.
-Three 90-minute integration psychotherapy sessions over the following three weeks. The first integration session will occur the day after the dosing session. These sessions will help the participant make sense of their psilocybin experience and apply insights to their daily lives. These sessions will be supported by the use of journaling or VR.
-Ongoing use of a reflective home journal or VR headset to support integration.
- Completion of online surveys at regular intervals throughout the trial.

Participants will be randomised to one of the three initial conditions: PAT with journaling, PAT with VR, or Waitlist (treatment as usual). Those in the Waitlist group will be randomised 10 weeks later into either into PAT with journaling, or PAT with VR. The VR headset or journal assignment will be random and is not based on participant preference.

The VR environment is a natural landscape that you can walk around in and it provides a method for expressing and recording insights from dosing and therapy sessions. Participants are advised to use the VR headset for about 15 minutes, 3-4 times a week but the exact duration and frequency is up to them.

The journaling group will be provided with a journal and will be encouraged to record, revisit and reflect on the contents of their psychedelic experience and therapy session. The duration and frequency of journaling is up to the participant.

Adherence to the intervention will be assessed by session attendance, completion of surveys and engagement with the VR or journaling tool.
Intervention code [1] 331193 0
Treatment: Drugs
Intervention code [2] 331419 0
Behaviour
Comparator / control treatment
Participants in the Waitlist group will continue with their treatment as usual and will commence the experimental part of the treatment after 10 weeks. Treatment as usual involves participants seeing their therapist at Psychology Care at the same frequency as before they were enrolled on to the trial.
Control group
Active

Outcomes
Primary outcome [1] 341666 0
Efficacy of a 6-week program of fly-in-fly-out psilocybin-assisted therapy (FIFO-PAT) compared to a treatment-as-usual (TAU) condition for MDD.
Timepoint [1] 341666 0
Week 10 post baseline
Secondary outcome [1] 449116 0
To determine any differences in depression remission rates between FIFO-PAT and TAU
Timepoint [1] 449116 0
Week 10 post baseline
Secondary outcome [2] 449117 0
Change in depression symptoms from baseline for the FIFO-PAT group compared to the TAU group
Timepoint [2] 449117 0
Week 2 (after prep 2), week 4 (after integration 1,) week 6 (after integration 3), week 8 and week 10 (primary endpoint visit) post baseline
Secondary outcome [3] 449118 0
Change in problematic alcohol use in FIFO-PAT compared to TAU
Timepoint [3] 449118 0
Baseline, week 10 post-baseline
Secondary outcome [4] 449119 0
Difference in frequency of treatment-emergent adverse events (e.g., Headache; Nausea; Fatigue; Visual distortions; Dry mouth; Dizziness; Increased blood pressure; Increased heart rate)
Timepoint [4] 449119 0
From Baseline to Week 10 post baseline, assessed weekly on average
Secondary outcome [5] 449122 0
Adherence rate, defined as the proportion of participants who complete the psilocybin dosing session, complete the primary endpoint, and complete at least 80% of other treatment sessions
Timepoint [5] 449122 0
Weeks 1 to 10 (early access) and weeks 11 to 20 (waitlist) post baseline
Secondary outcome [6] 449123 0
Post FIFO-PAT ratings of treatment acceptability
Timepoint [6] 449123 0
Week 10 (early access) or week 20 (waitlist) post baseline
Secondary outcome [7] 449124 0
Changes in work absenteeism and performance
Timepoint [7] 449124 0
Baseline, Week 36 (early access) or week 46 (waitlist) post-baseline
Secondary outcome [8] 449636 0
Difference in depression response rates between FIFO-PAT and TAU
Timepoint [8] 449636 0
Baseline, Week 10 post-baseline
Secondary outcome [9] 449637 0
Difference in Healthcare Utilization changes between FIFO-PAT and TAU
Timepoint [9] 449637 0
Baseline, Week 36 (early access) or week 46 (waitlist) post baseline
Secondary outcome [10] 449638 0
Difference in quality of life changes between FIFO-PAT and TAU
Timepoint [10] 449638 0
Baseline, Week 36 (early access) or week 46 (waitlist) post baseline
Secondary outcome [11] 449681 0
Difference between FIFO-PAT and TAU in changes cigarette use
Timepoint [11] 449681 0
Baseline, week 10 post baseline
Secondary outcome [12] 449682 0
Difference between FIFO-PAT and TAU in changes problematic drug use
Timepoint [12] 449682 0
Baseline, week 10 post baseline
Secondary outcome [13] 449683 0
Difference between FIFO-PAT and TAU in changes functional outcomes use
Timepoint [13] 449683 0
Baseline, week 10 post baseline
Secondary outcome [14] 449684 0
Difference between FIFO-PAT and TAU in changes in anxiety symptoms
Timepoint [14] 449684 0
Baseline, week 10 post baseline
Secondary outcome [15] 449685 0
Difference between FIFO-PAT and TAU in changes in problematic physical symptoms
Timepoint [15] 449685 0
Baseline, week 10 post baseline
Secondary outcome [16] 449687 0
Difference between FIFO-PAT and TAU in changes in suicidality
Timepoint [16] 449687 0
Baseline to Week 10 post baseline, weekly on average
Secondary outcome [17] 449688 0
Prevalence of Hallucinogen Persisting Perceptual Disorder symptoms
Timepoint [17] 449688 0
Week 36 (early access) or week 46 (waitlist) post baseline
Secondary outcome [18] 450032 0
Post FIFO-PAT ratings of treatment satisfaction
Timepoint [18] 450032 0
Week 10 (early access) or week 20 (waitlist) post baseline

Eligibility
Key inclusion criteria
- Be aged 18 to 75 years.
- Meet DSM-5 criteria for Major Depressive Disorder
- Score at least 20 on the MADRS at screening
- Be engaged in psychological services at the trial partner clinic, have completed at least four sessions, and attend at least monthly on average.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Have a current or lifetime history of meeting DSM-5 criteria for Schizophrenia, other Psychotic Disorder, Dissociative Identity Disorder, or Bipolar I or II Disorder or other mood disorder with psychotic features.
- Have a current or past year history of meeting DSM-5 criteria for alcohol or drug dependence (excluding caffeine and nicotine), if determined by the PI or Study Physician to be incompatible with safe exposure to psilocybin.
- Have current serious suicide risk, as determined through psychiatric interview, responses to Columbia Suicide Severity Rating Scale (C-SSRS), and clinical judgment of the AP or treating team
- Require ongoing concomitant therapy with an excluded medication.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by independent randomisation monitor (research staff not otherwise involved in trial)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software, stratified by age, sex assigned at birth, and duration of illness.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
POWER ANALYSIS
We calculated Cohen’s d for the primary endpoint (MADRS at Day 43) in Raison et al. (2023, JAMA), using data from the main article Table 2. The psilocybin group (n=52) had a mean MADRS change of -19.1 (SD=11.3), and the niacin group (n=47) had -6.8 (SD=10.6), yielding a mean difference of -12.3. Using the pooled SD (10.97), Cohen’s d = 12.3 / 10.97 ˜ 1.12.

t tests - Means: Difference between two independent means (two groups)
Analysis: A priori: Compute required sample size
Input: Tail(s) = Two
Effect size d = 1.12
a err prob = 0.05
Power (1-ß err prob) = 0.8
Allocation ratio N2/N1 = 0.5
Output: Noncentrality parameter d = 2.9692872
Critical t = 2.0484071
Df = 28
Sample size group 1 = 20
Sample size group 2 = 10
Total sample size = 30
Actual power = 0.8175656

OTHER STATISTICAL METHODS
A full Statistical Analysis Plan will be pre-registered before completion of the trial and data lock. Primary and secondary continuous outcomes (e.g., MADRS, PHQ-9) will be analysed using linear mixed-effects models with fixed effects for treatment group, time, and their interaction. Binary outcomes (e.g., response and remission rates) will be analysed using logistic regression. All models will adjust for relevant covariates (e.g., baseline severity) where appropriate. Analyses will be conducted under the modified intent-to-treat principle, including all randomised participants with available data. Safety and tolerability outcomes will be summarised descriptively and compared between groups using appropriate parametric or nonparametric tests depending on data distribution.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/08/2025
Actual
Date of last participant enrolment
Anticipated
2/02/2026
Actual
Date of last data collection
Anticipated
6/12/2027
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 319107 0
University
Name [1] 319107 0
Monash University
Country [1] 319107 0
Australia
Funding source category [2] 319151 0
Commercial sector/Industry
Name [2] 319151 0
White Rabbit Ventures
Country [2] 319151 0
Australia
Funding source category [3] 319152 0
Commercial sector/Industry
Name [3] 319152 0
Enosis Therapeutics
Country [3] 319152 0
Australia
Funding source category [4] 319153 0
Commercial sector/Industry
Name [4] 319153 0
PsychologyCare
Country [4] 319153 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 321612 0
None
Name [1] 321612 0
Address [1] 321612 0
Country [1] 321612 0
Other collaborator category [1] 283537 0
Commercial sector/Industry
Name [1] 283537 0
Psychology Care
Address [1] 283537 0
Country [1] 283537 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317704 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 317704 0
Ethics committee country [1] 317704 0
Australia
Date submitted for ethics approval [1] 317704 0
18/02/2025
Approval date [1] 317704 0
19/05/2025
Ethics approval number [1] 317704 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 141870 0
Dr Paul Liknaitzky
Address 141870 0
Clinical Psychedelic Lab, Level 1, Building 2, 270 Ferntree Gully Rd, Notting Hill VIC
Country 141870 0
Australia
Phone 141870 0
+61 3 9905 2038
Fax 141870 0
Email 141870 0
[email protected]
Contact person for public queries
Name 141871 0
Paul Liknaitzky
Address 141871 0
Clinical Psychedelic Lab, Level 1, Building 2, 270 Ferntree Gully Rd, Notting Hill VIC
Country 141871 0
Australia
Phone 141871 0
+61 3 9905 2038
Fax 141871 0
Email 141871 0
[email protected]
Contact person for scientific queries
Name 141872 0
Paul Liknaitzky
Address 141872 0
Clinical Psychedelic Lab, Level 1, Building 2, 270 Ferntree Gully Rd, Notting Hill VIC
Country 141872 0
Australia
Phone 141872 0
+61 3 9905 2038
Fax 141872 0
Email 141872 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.