Psilocybin for Treatment-Resistant Depression in Autism with Pre-Post Brain and Cognitive Measurement to Understand Mechanisms

Phase 1

Recruiting

• Conditions: Treatment Resistant Depression; Autism Spectrum Disorder
• Interventions: Drug: Psilocybin

• Registration Number: NCT06731621
• Lead Sponsor: Centre for Addiction and Mental Health

Brief Summary

We propose a first-of-its-kind open-label clinical trial to investigate the feasibility, tolerability, and safety of administering psilocybin in autistic adults with treatment-resistant depression (TRD). In this study, 20 participants (intellectually able and fluent-speech adults) with autism and co-occurring TRD will receive around 20 hours of manualized psychotherapy that has previously been used with psilocybin (Agin-Liebes et al., 2020). They will also receive psilocybin at 2 different time points, firstly a safety dose of 10mg, followed by a treatment dose of 25mg. This study design is in accordance with previous studies investigating the use of psilocybin with psilocybin-assisted therapy (PAT) to treat TRD (Carhart-Harris et al., 2016, 2018)

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-07
• Study Start: 2024-11-01
• Study First Submitted: 2024-11-19
• Study First Submitted QC: 2024-12-09
• Study First Posted: 2024-12-12
• Last Update Submitted: 2025-02-21
• Last Update Posted: 2025-02-24
• Primary Completion: 2027-08
• Study Completion: 2027-08

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Autistic adult, ages 18-65
• Must be deemed to have capacity to provide informed consent;
• Must sign and date the informed consent form;
• Stated willingness to comply with all study procedures;
• Intellectually able: Either 1) the participant has a previous report showing intelligence quotient (IQ) ≥ 70 on the General Abilities Index of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) or any other standardized intelligence scales, or 2) the participant scores >10 percentile on the nine-item form of the Raven's Standard Progressive Matrices Test (RSPM).
• Ability to read and communicate 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;
• Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the Structured Clinical Interview for DSM-5 (Clinician Version; SCID-5-CV) administered at the first screening visit (V1);
• Participants diagnosed with treatment-resistant depression defined as individuals with a baseline GRID-HAMD-17 score > 14 and that have not responded to two or more separate trials of antidepressants at an adequate dosage and duration based on the Antidepressant Treatment History Form (ATHF; Appendix C2); there is no upper limit on the number of treatment failures;
• Ability to take oral medication;
• Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 3 months prior to screening and agreement to use such a method during study participation;
• Individuals who are willing to taper off current antidepressant and antipsychotic medications for a minimum of 2-weeks (or more depending on the medication) prior to Baseline (V2) and whose physician confirms that it is safe for them to do so; and
• Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration.

Exclusion Criteria

• Pregnant as assessed by a urine pregnancy test at Screening (V1) or individual's that intend to become pregnant during the study or are breastfeeding;
• Treatment with another investigational drug or other intervention within 30 days of Screening (V1);
• The presence of an unstable seizure disorder as defined by having not been seizure-free for at least 6 months or anticonvulsant treatment has not been stable for at least 4 weeks;
• The presence of any clinically significant or unstable medical conditions, including cardiovascular, liver, kidney, pulmonary disease, presence of known congenital brain malformation, as per investigator assessment based on medical history and chart review;
• Moderate or severe DSM-5 diagnosis of an alcohol or substance use disorder in the past 12 months;
• Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, or neurocognitive disorder as determined by medical history and the SCID-5-CV clinical interview;
• Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder as determined by the family medical history form and discussions with the participant;
• Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment;
• Substantial lifetime use (>10 years total) or recent use (past 6 months) of ketamine, psychedelics, or MDMA;
• Any other clinically significant physical illness, including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study;
• Have active suicidal ideation with intent and plan as determined by SBQ-ASC.
• Are currently undergoing psychotherapy or have undergone psychotherapy within 12 weeks prior to Screening.
• Contraindication to MR imaging: with shrapnel or other metal or electronic implants in their bodies (such as pacemakers, aneurysm clips, surgical devices, metallic tattoos on the head, etc.) or a previous history of claustrophobia.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label	Psilocybin	Safety Dosing Session (V3): 10mg of psilocybin + therapy + safety evaluations Active Treatment Session (V4): 25mg of psilocybin + therapy + safety evaluations

Primary Outcome Measures

Name	Time	Method
Feasibility of Administering Psilocybin in Conjunction with Psychotherapy in Autistic Adults	From enrollment to end of treatment & follow-up at 12 weeks post-intervention	Percentage of participants recruited and retained.
Number of Participants with Treatment-Related Adverse Events as Assessed by SBQ-ASC & UKU Side Effect Rating Scale	From enrollment to end of treatment & follow-up at 12 weeks post-intervention	Treatment-Related Adverse Events are expected to be similar in nature \& frequency to those reported in previous clinical studies on classic psychedelics in neurotypical populations.; The UKU Side Effect Scale will be used to capture \& document core features of any treatment-related side effects. The Suicidal Behaviors Questionnaire - Autism Spectrum Conditions (SBQ-ASC) will be used to measure suicidality in participants. It consists of 5 scored items: 1) lifetime experience of suicidal thoughts; 2) frequency of intense suicidal thoughts in the last 12 months; 3) perseverative intense suicidal thoughts; 4) likelihood of suicide attempts; 5) communication of future suicide intent \& past suicide attempts to others. The SBQ-ASC also includes optional follow-up items which are not scored, based on responses to Item 5: for those who have attempted suicide, the follow-up items address presence of plans, impulsivity, and access to means.
Feasibility of Dense Sampling Brain MRI Procedures & Trial Design	From enrollment to end of treatment & follow-up at 12 weeks post-intervention	Percentage of participants recruited and retained for the optional dense sampling brain MRI procedures (multiple scans throughout duration of participant's involvement in study, up to 10 ).

Secondary Outcome Measures

Name	Time	Method
Subjective Psychedelic Effects as Measured by the 11-Dimensions of Altered States of Consciousness (11D-ASC) Rating Scale	Administered following each dosing session (Visit 3 & Visit 4)	A visual analogue scale (0-100 millimeters in length) with higher scores indicating more intense effects. Each question is attributable to one of the specified 11 dimensions of altered states of consciousness.
Changes in Brain Network Interactions as Assessed with Pre- and Post-Intervention MRI Brain Scans	Evaluated using MRI following intervention, Visit 5	Brain MRI scans and subsequent brain network \& cognitive modelling will be used to assess \& study changes in brain network interactions and possible mechanisms underpinning antidepressant effects of psilocybin for treatment-resistant depression in autism.
Changes & Variance in Brain Functional Connectivity Assessed Across Dense Sampling Brain MRI Sessions	From enrollment to end of treatment & follow-up at 12 weeks post-intervention	The optional dense sampling brain MRI procedures will allow for a more robust model of the brain and changes/variance that may be observed in an individual's brain over the course of the study, particularly in response to the intervention. Brain MRI scans and subsequent brain network \& cognitive modelling will be used to assess \& study changes in brain network interactions and possible mechanisms underpinning antidepressant effects of psilocybin for treatment-resistant depression in autism.

Trial Locations

Locations (1)

Centre for Addiction and Mental Health; 🇨🇦 Toronto, Ontario, Canada