Psilocybin rTMS for Treatment Resistant Depression
Phase II, randomised 2x2 factorial study (n=100) testing COMP360 psilocybin (25 mg vs 1 mg) combined with active or sham accelerated iTBS (SAINT/SNT) in treatment-resistant MDD.
This phase II, randomized 2x2 factorial trial (device × dose) will enroll 100 participants with treatment-resistant major depressive disorder to evaluate safety, feasibility, and efficacy of sequencing COMP360 psilocybin therapy with accelerated intermittent theta burst stimulation (aiTBS/SAINT).
Participants receive psychological preparation (two sessions), a single psilocybin dosing session (~6–8 hours) with integration sessions, followed the next week by either active aiTBS (10 sessions/day for 5 days) or sham aiTBS. Neurobiological assessments (fMRI, EEG) occur at baseline, 2 days post-psilocybin, and ~14 days post-psilocybin/after aiTBS.
Primary aims are to determine safety and feasibility of sequencing treatments and to test whether the combination demonstrates superior acute and sustained antidepressant effects; additional aims include examining neurobiological and inflammatory biomarker changes and moderators of response.
Study Protocol
Preparation
2 sessions
90 min each
Locations
Health Discovery Building (HDB), 1601 Trinity St., Bldg B., Z0600 — Austin, Texas, United States
Dosing
1 sessions
420 min each
Integration
2 sessions
60 min each
Therapeutic Protocol
support
Study Arms & Interventions
25mg + active aiTBS
experimental
COMP360 25 mg capsule followed by active accelerated iTBS (SAINT/SNT) delivered 10 sessions/day for 5 days.
Interventions
Psilocybin25 mg
via Oral• single dose
COMP360 25 mg capsule; single dosing session (~6-8 hours).
Compound
via Other• daily for 5 days
Active aiTBS (SAINT/SNT) targeted to fMRI-guided left DLPFC; 10 sessions/day for 5 consecutive days at 90% depth-corrected RMT.
25mg + sham aiTBS
active comparator
COMP360 25 mg capsule with sham iTBS delivered in same schedule.
Interventions
Psilocybin25 mg
via Oral• single dose
COMP360 25 mg capsule; single dosing session (~6-8 hours).
Compound
via Other• daily for 5 days
Sham aiTBS delivered to mimic active SAINT/SNT without brain stimulation.
1mg + active aiTBS
active comparator
Low-dose COMP360 (1 mg) with active aiTBS (SAINT/SNT).
Interventions
Psilocybin1 mg
via Oral• single dose
Low-dose COMP360 1 mg capsule.
Compound
via Other• daily for 5 days
Active aiTBS (SAINT/SNT) as per protocol.
1mg + sham aiTBS
active
Low-dose COMP360 (1 mg) with sham iTBS.
Interventions
Psilocybin1 mg
via Oral• single dose
Low-dose COMP360 1 mg capsule.
Compound
via Other• daily for 5 days
Sham aiTBS delivered to mimic active condition.
Participants
Ages
22 – 65
Sexes
Male & Female
BMI
-
Psychosis History
Allowed
Inclusion Criteria
Inclusion Criteria:
1. Adults, ages 22-65.
2. English language comprehension suitable to understand experimenter instructions and to communicate to study personnel/staff reasonably easily.
3. Current major depressive episode (without psychotic features), either as part of recurrent major depressive disorder (MDD) or single episode MDD with current episode present for at least the past 3 months (as determined by the Structured Clinical Interview for DSM-5; SCID-5).
4. Montgomery Asberg Depression Rating Scale (MADRS) score of 20 or greater at baseline assessment (at least moderate severity).
5. Treatment-resistant MDD, as defined by 2 or more failed trials of an antidepressant prescribed and taken for an adequate dose and duration for the current major depressive episode as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).
6. Willingness and ability to attend daily, full-day visits to the research site for a period of ~2 weeks and to participate in all study procedures (clinical assessments, treatments, and neurobiological assessments).
7. If currently taking an antidepressant medication (an SSRI, SNRI, or atypical antidepressant), antipsychotic, and/or other augmenting medication (e.g., lithium), willingness to discontinue medication(s) over a 2-8 week period with the assistance of study staff and maintain at least a 2-5 week period (5-week period for fluoxetine) off of medications prior to the baseline visit AND willingness to remain off medications for a period of 1 month following the end of the treatment course (approximately 6-8 weeks after the baseline visit).
Exclusion Criteria
Exclusion Criteria:
1. Prior history or current diagnosis of a psychotic disorder (including MDD with psychotic features), bipolar disorder, or personality disorder (based on medical history, clinician judgement, SCID-5 and/or SCID for Personality Disorders).
2. Current diagnosis of posttraumatic stress disorder, acute stress disorder, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, or alcohol or substance-use disorder.
3. Having met criteria for an alcohol or substance-use disorder within the past year.
4. Use of electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulation during the current major depressive episode.
5. Any prior rTMS treatment (10Hz, 5Hz, 1Hz, or conventional intermittent theta burst).
6. Current participation in an evidence-based psychotherapy for major depression (e.g., cognitive behavioral therapy, behavioral activation). Ongoing supportive psychotherapy is allowable if maintained at the same frequency throughout the duration of the short-term follow-up clinical endpoint (1 month after treatment cessation) of the study and if no recent change in therapy type or frequency for 1 month prior to enrollment.
7. Exhibiting significant suicide risk within the past 12 months, at screening, or at baseline, as evidenced by: a) suicidal ideation with some intent to act but no specific plan (item #4 from the Columbia Suicide Severity Rating Scale; C-SSRS); b) suicidal ideation with intent to act and a specific plan (item #5 from the C-SSRS); c) suicide attempt or non-suicidal self-injury requiring medical attention in the past 12 months; or d) self-report of significant suicidal ideation with intent or significant non-suicidal self-injury during screening or baseline clinical interview.
8. Major depressive episode that is secondary to a medication or a general medical condition, as judged by investigators.
9. Any other factors, such as major medical conditions, unstable housing or threatening life circumstances, erratic behavior, etc. that are judged by the investigators to be a significant barrier to participation in the study protocol and/or to establishing therapeutic rapport necessary for safe administration of psilocybin.
10. Prior past-year ingestion of a serotonergic psychedelic, e.g., psilocybin, LSD, mescaline, dimethyltryptamine, etc. or more than 5 lifetime ingestions of a serotonergic psychedelic on separate occasions.
11. Participant unwillingness to not ingest or use additional serotonergic psychedelics outside the context of study procedures for the duration of the study follow-up period (12 months).
12. Ferrous metal, metallic implants, or implanted medical devices that would preclude administration of rTMS and/or participation in MRI procedures, including but not limited to: cochlear implants, implanted brain stimulators, aneurysm clips.
13. Past history of seizures or epilepsy (rTMS risk).
14. Neurological disorder, including epilepsy, stroke, or history of brain surgery.
15. Past penetrating brain injury or any head injury resulting in a loss of consciousness for 30 minutes or more or post-concussive symptoms for more than seven days following a head injury.
16. Head injury in the past two months, regardless of severity.
17. Currently pregnant and/or nursing or about to become pregnant. A positive urine pregnancy test at screening and/or baseline will lead to participant exclusion from the study.
18. Engagement in sexual intercourse which could result in pregnancy without use of a highly effective contraceptive method throughout participation in the study and for at least three months after COMP360 (psilocybin) administration.
19. Severe claustrophobia (prohibiting MRI acquisition).
20. Uncontrolled hypertension (resting blood pressure > 140/90 mm hg).
21. Uncontrolled thyroid disease as indicated by unstable thyroid hormone dosage < 3 months prior to screening, or abnormal and clinically significant thyroxine (FT4) levels (a free FT4 measurement will be conducted for all participants with an out-of-range thyroid-stimulating hormone [TSH] value irrespective of thyroid history).
22. Lifetime history of cardiomyopathy, stroke, heart disease, heart attack, tachycardia, elongated QT-interval corrected by Friderichia (> 450ms for men and > 470ms for women); clinically significant cardiac arrhythmia within 1 year of study entry; and/or abnormal electrocardiogram on study entry.
23. Type I diabetes mellitus or uncontrolled Type II diabetes mellitus (defined by hemoglobin A1c > 8% at screening) or a history of diabetic ketoacidosis, hyperglycemic coma, or severe hypoglycemia with loss of consciousness (< 3 months prior to signing of consent form).
24. Positive urine drug screening for drugs of abuse at screening and/or baseline will trigger a review with participant and assessment for eligibility based on pattern of use and willingness to abstain in conjunction with medical monitor and investigative team.
25. Clinically-significant results from physical examination, blood test, urine test, vital signs, or ECG at screening and/or baseline.
26. Current enrollment in another interventional study or participation within such a study within 6 months of screening.
27. Self-reported hypersensitivity to psilocybin or another serotonergic psychedelic.