ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12625001368426

Ethics application status

Approved

Date submitted

10/11/2025

Date registered

8/12/2025

Date last updated

8/12/2025

Date data sharing statement initially provided

8/12/2025

Type of registration

Prospectively registered

Titles & IDs

Public title

Path-OUD: Psilocybin-Assisted Therapy for people living with Opioid Use Disorder.

Scientific title

Psilocybin-assisted therapy effects on non-prescribed opioid use and brain and cognitive health in people with Opioid Use Disorder engaged in opioid agonist treatment.

Additional trial identifiers [1]

Therapeutic Goods Association (TGA) CTN: 04457-1

Additional trial identifiers [2]

Funder - Wellcome Leap; Pure ID: 673473525

Universal Trial Number (UTN)

Trial acronym

Path-OUD

Related trial records

Health condition

Health condition(s) studied:

Opioid Use Disorder (OUD)

Condition category

Condition code

Mental Health

Addiction

Intervention/exposure

Study type

Interventional

Description of the intervention or exposure

Background: The intervention consists of a single oral administration of psilocybin (30 mg) in capsule form. Dosing is embedded in a standardised psychotherapeutic framework (Psychedelic Assisted Therapy/PAT) that includes preparatory and integration sessions. Preparation, treatment, and integration sessions will be delivered by two qualified and PAT trained therapists.

Preparation sessions: Preparation session 1 occurs one week prior to dosing and preparation session 2 occurs one day prior to dosing. Preparation session 1 includes rapport building, participant history taking, including mental health and drug use, and psychoeducation about PAT and psilocybin. Preparation session 2 includes strengthening rapport, introduction to the PAT model which draws from an Acceptance and Commitment (ACT) paradigm; including concepts of mindfulness, observing self, and intention setting (in line with values). Exploration of managing difficult experiences on dosing day, therapeutic touch consent, and practicalities of dosing day, including after care and integration are also delivered. Each preparation session is 2 hours.

Dosing session: The dosing session occurs the day after preparation session 2 and is facilitated by the therapists. The dosing session takes place in a controlled, safe, quiet, comfortable and furnished room with therapists present at all times (except for bathroom breaks). The participant initially settles in with meditation, and coping skills and intention are reviewed by the therapists. The psilocybin capsule is taken approximately one hour after arriving. Participants ingest the psilocybin capsule with approximately 200ml of water. Dose and administration procedures are standardised across participants. The participant is encouraged to get comfortable, for example through sitting or lying on a bed, adjusting lighting, using eye shades and headphones to facilitate the 'internal' experience. Therapists ensure the participant remains in the room and not left alone during the psilocybin experience. Participants can opt to have the therapists beside them if needed and therapeutic touch (i.e. not beyond shoulder to hand) may be applied in line with the participants prior documented consent. Blood pressure, temperature and comfort are monitored regularly throughout the session. The dosing session is approximately 6-8 hours. A study doctor will provide medical review and oversight.

Integration sessions: In line with PAT standards, participants are invited to 3 x 60-minute integration sessions. The first integration session will occur one day post dosing session and invites the participant to share insights of their dosing day experience without judgment and with curiosity. Therapists provide post dose information and structured psychological support. Integration session two and three will occur within 3 weeks post dosing session. These sessions centre on processing and making meaning from the psilocybin experience aligning with the values-based intentions outlined by the participant. Participants are encouraged to set goals and consider future support.

Mode of delivery: The intervention is delivered individually to each participant in-person or via telehealth for the integration sessions where in-person is not possible. Integration sessions can be delivered by one qualified and PAT trained therapist when necessary.

Intervention adherence, fidelity and tolerance: Adherence will be determined through attendance at all scheduled treatment (PAT) sessions. Fidelity will be maintained through standardised assessment schedules, therapeutic procedures and audio-visual recording during the dosing sessions. Safety and tolerability will be tracked with physiological observation (e.g. blood pressure, pulse, temperature), adverse event monitoring, and validated clinical rating scales.

Intervention code [1]

Treatment: Drugs

Description of the comparator or control

Low Dose Comparator - Psilocybin (1mg) as part of Psychedelic-Assisted Therapy.

Control group

Active

Outcomes

Primary outcome [1]

Number of days of non-prescribed opioid use in the past 30 days at 12 weeks, adjusted for baseline consumption (past 30 days prior to baseline).

Timepoint [1]

Baseline and 12 weeks (primary endpoint) following Psilocybin Dosing Session.

Secondary outcome [1]

Adherence to Medication-Assisted Treatment of Opioid Dependence (MATOD).

Timepoint [1]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [2]

Number of days of non-prescribed opioid use in the past 30 days at study timepoints (baseline to 6-month follow up period).

Timepoint [2]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [3]

Craving.

Timepoint [3]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [4]

Craving.

Timepoint [4]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [5]

Impulsivity.

Timepoint [5]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [6]

Substance abuse - self stigma.

Timepoint [6]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [7]

Impulsive responding: Attentional control.

Timepoint [7]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [8]

Impulsive responding: Information gathering.

Timepoint [8]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [9]

Impulsive responding: Feedback monitoring.

Timepoint [9]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [10]

Impulsivity/Delay gratification.

Timepoint [10]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [11]

Working memory.

Timepoint [11]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [12]

Cue reactivity evoked brain activity and effective (directed) connectivity.

Timepoint [12]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [13]

Emotional face processing.

Timepoint [13]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [14]

Structural morphometry.

Timepoint [14]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [15]

White matter measures.

Timepoint [15]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [16]

Change in resting state and naturalistic brain directed connectivity.

Timepoint [16]

1 day before Psilocybin Dosing Session (Baseline), 1 day after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session.

Secondary outcome [17]

Intelligence.

Timepoint [17]

Baseline.

Secondary outcome [18]

Depression.

Timepoint [18]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [19]

Anxiety.

Timepoint [19]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [20]

Trauma Experiences.

Timepoint [20]

Baseline.

Secondary outcome [21]

Post-Traumatic Stress Disorder.

Timepoint [21]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [22]

Affect.

Timepoint [22]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [23]

Quality of Life.

Timepoint [23]

Baseline, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [24]

Psychological flexibility.

Timepoint [24]

Baseline, 1 week after Psilocybin Dosing Session, 2 weeks after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session, 8 weeks after Psilocybin Dosing Session, 12 weeks after Psilocybin Dosing Session, and 6 months after Psilocybin Dosing Session.

Secondary outcome [25]

Therapeutic alliance.

Timepoint [25]

Baseline, 1 week after Psilocybin Dosing Session.

Secondary outcome [26]

Psychedelic Trait Measure (Trait absorption).

Timepoint [26]

Baseline, 4 weeks after Psilocybin Dosing Session.

Secondary outcome [27]

Personality.

Timepoint [27]

Baseline, 2 weeks after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session.

Secondary outcome [28]

Personality.

Timepoint [28]

Baseline, 2 weeks after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session.

Secondary outcome [29]

Psychedelic Trait Measure (Mindset).

Timepoint [29]

1 day after Psilocybin Dosing Session, 2 weeks after Psilocybin Dosing Session and 4 weeks after Psilocybin Dosing Session.

Secondary outcome [30]

Self compassion.

Timepoint [30]

Secondary outcome [31]

Psychedelic Trait Measure (Mindfulness).

Timepoint [31]

Baseline, 2 weeks after Psilocybin Dosing Session, 4 weeks after Psilocybin Dosing Session.

Eligibility

Key inclusion criteria

1. Aged 18-60 inclusive.

2. Meets DSM-5 criteria for Opioid Use Disorder, as assessed using QuickSCID-5.

3. Have been on a MATOD program for at least 2 months prior to screening interview.

4. Methadone/buprenorphine average daily dose (or equivalent weekly/monthly dose in the case of long-acting injectable buprenorphine) has varied by no more than 20% in the 2 weeks prior to screening interview.

5. Willingness to remain on a stable dose of methadone/buprenorphine up to dosing day.

6. Use of non-prescribed opioids more than 6 times on average across the 30-day period or at the judgement of the study clinician prior to screening interview.

7. Have a breath alcohol concentration less than or equal to 0.01% at screening - this may be re-evaluated during the study period, at the judgement of the study clinician.

8. Agree to refrain from non-prescribed psychotropic substance or illicit drug use for at least 72 hours prior to Psilocybin Dosing Session, with the exception of moderate use of alcohol, cannabis, nicotine, and caffeine.

9. Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the Psilocybin Dosing Session unless approved by the study clinician.

10. Are proficient in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent.

11. Have the capacity to engage with, and consent to the study requirements and are able attend all study visits.

12. Must consent to the study investigators contacting their primary treating health practitioner(s) for the purpose of corroborating medical history and their MATOD dosing pharmacy for the purpose of cross-validation of self-reported MATOD adherence.

13. Have a family member or friend who can assist with transportation and activities of daily living after the Psilocybin Dosing Session.

Minimum age

18 Years

Maximum age

60 Years

Sex

Both males and females

Healthy volunteers

Key exclusion criteria

1. Currently pregnant, planning pregnancy, or breastfeeding.

2. Participation in clinical trial and receipt of investigational drug(s) during 30 days prior to the research study, except as explicitly approved by the study clinician.

3. Currently meets DSM-5 criteria for moderate to severe Substance Use Disorder (SUD) for substances other than opioids, alcohol, cannabis or nicotine. Patients with comorbid Alcohol Use Disorder (AUD) will be accepted if their AUD is not severe enough to require a medicated alcohol detoxification.

4. Any use of serotonergic psychedelics in the past 6 months or more than 50 uses of any serotonergic psychedelics in lifetime.

5. More than mild opioid withdrawal (COWS > 12).

6. Have a known allergy or hypersensitivity to psilocybin or any of the materials contained in the capsule used in the study.

7. Have an allergy, hypersensitivity, or other contraindication that would preclude safe treatment of acute hypertension, anxiety, or psychotic symptoms using standard medical interventions if necessary during or immediately after Psilocybin Dosing Session.

8. Meets current or lifetime DSM-5 criteria for schizophrenia or any psychotic disorder, or organic mental disorder, or has a first-degree family history of psychotic disorder. This includes hallucinogen-persistent perception disorder.

9. Meets current or lifetime DSM-5 criteria for bipolar disorder or has first degree family history of bipolar disorder.

10. Meets current DSM-5 criteria for severe Major Depressive Disorder (MDD); or current or lifetime DSM-5 criteria for MDD with psychotic features. Mild and moderate MDD as well as MDD in stable remission are allowed if no suicidal risk, in the clinical judgement of the study clinician.

11. Have current serious suicide risk, as determined by responses to Columbia Suicide Severity Rating Scale (C-SSRS) and/or the clinical judgement of the study clinician or the treating team.

12. Presence of any other psychiatric condition that, in the opinion of the study clinician, may interfere with completion of the study or place the patient at heightened risk.

13. Have a history of or have a current medical condition which – based on the judgement of the study clinician - would make a participant unsuitable for the study. This includes, but is not limited to, the following:
a. Significant hepatocellular injury (except for patients with documented Gilberts syndrome)
b. Significant renal injury
c. Significant cardiovascular history/active cardiovascular conditions (e.g. high blood pressure, congenital long QT syndrome, coronary artery disease, cardiac ischemia, myocardial infarction, cardiac hypertrophy, congestive heart failure, tachycardia, ECG abnormalities, artificial heart valve)
d. Significant pulmonary illness (e.g. COPD)
e. Significant endocrine condition (e.g. insulin-dependent diabetes, hyperthyroidism)
f. Significant gastrointestinal illness (e.g. Crohn’s disease)
g. Seizure disorder or history of seizures not related to drug or alcohol withdrawal (excluding childhood febrile seizure)
h. History of serious head trauma or injury causing significant loss of consciousness and/or associate with skull fracture or intracranial bleeding or abnormal MRI
i. Current HIV infection
j. Weighs < 48kg or BMI < 17.

14. Participants who present with contraindications to MRI scanning (including, but not limited to, magnetically active implants or devices, significant claustrophobia, or non-removable skin patches) may be excluded from participation in the MRI component of the study, as determined by the study clinician or radiologist.

15. Has received medication that could interact adversely with psilocybin (e.g. inhibitors of UGT1A9, UGT1A10, MAO and aldehyde or alcohol dehydrogenase) within the time of administration of study agent, based on the guidance of the study clinician.

16. Current use of psychoactive medications that in the study clinician’s judgement would meaningfully affect safety or effectiveness of trial medications (e.g. antipsychotics, mood stabilisers, stimulants). Antidepressants and PRN medications (e.g. short-acting benzodiazepines, z-drugs) may be permitted at the discretion of the study clinician, where safe and appropriate.

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 computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation (randomly chosen from sizes three or six). Participants will be randomised in a 2:1 ratio (Psilocybin 30 mg : Psilocybin 1 mg).

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes

Intervention assignment

Parallel

Other design features

Phase

Phase 1 / Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

Power analysis was conducted for a two-arm design comparing high-dose psilocybin (PSI-30 mg) with a low-dose comparator (PSI-1 mg). Previous clinical studies have demonstrated large treatment effects of psilocybin on substance-use and mood-related outcomes (Cohen’s d > 0.7; Carhart-Harris et al., 2016; 2021).

To ensure a conservative estimate, this trial was powered to detect an effect size of d = 0.67 with power = 80% and Type I error = 0.05. Power calculations were performed in R (v4.3) using the pwr package, and involving 10,000 model iterations, indicating that a total n = 24 (16 PSI-30 mg; 8 PSI-1 mg) provides sufficient power to detect group differences of this magnitude. To allow for an estimated 30% attrition rate, the sample size was inflated to yield a target enrolment of 36 participants.

Descriptive statistics will summarise demographic and baseline variables. Between-group comparisons will be assessed using independent-samples t-tests for normally distributed data or Wilcoxon rank-sum tests for non-normal data. Categorical variables (e.g., medication adherence category) will be compared using chi-squared tests or odds ratios, as appropriate.

The primary analysis model will examine reductions in non-prescribed opioid use, assessed using the TLFB and cross-validated with biological indices. A mixed-effects model for repeated measures (MMRM) will include fixed effects for treatment group, time, and their interaction, and a random intercept for participants to account for within-subject variability.

Sensitivity analyses will be performed to test model assumptions using an ANCOVA model. Multiple imputation will be used to address all missing data. The delta increment approach will be used to evaluate patterns of missingness assumptions.

Secondary and Exploratory outcomes will be analysed using the primary analysis model. Treatment fidelity will be analysed via logistic regression.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

19/12/2025

Actual

Date of last participant enrolment

Anticipated

30/04/2027

Actual

Date of last data collection

Anticipated

30/04/2028

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Wellcome Leap

Address [1]

Country [1]

United States of America

Primary sponsor type

University

Name

Monash University

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash University Human Research Ethics Committee

Ethics committee address [1]

https://www.monash.edu/research-ethics-and-integrity/human-ethics

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

15/09/2025

Ethics approval number [1]

47710

Summary

Brief summary

This study explores whether a single 30mg dose of Psilocybin - when given as part of Psychedelic-Assisted Therapy - can assist people who are living with Opioid Use Disorder reduce their use of non-prescribed opioids. The study will also use functional Magnetic Resonance Imaging (fMRI) to observe any changes in participants’ brain, thinking and mood.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Adeel Razi

Address

770 Blackburn Road, Monash University, Clayton, Victoria, 3168

Country

Australia

Phone

+61399050109

Fax

[email protected]

Contact person for public queries

Name

Adeel Razi

Address

770 Blackburn Road, Monash University, Clayton, Victoria, 3168

Country

Australia

Phone

+61 03 99050100

Fax

[email protected]

Contact person for scientific queries

Name

Adeel Razi

Address

770 Blackburn Road, Monash University, Clayton, Victoria, 3168

Country

Australia

Phone

+61 399050100

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
• Requires approval by an ethics committee

What individual participant data might be shared?

• All de-identified individual participant data

What types of analyses could be done with individual participant data?

• Any type of analysis (i.e. no restrictions on data re-use)

When can requests for individual participant data be made (start and end dates)?

From:
After publication of main results
To:
Not yet decided

Where can requests to access individual participant data be made, or data be obtained directly?

• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?

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.

Trial Review

Documents added manually

Documents added automatically