Psilocybin + rTMS for Depression

(PSILOBSD Trial)

Overseen By Gregory A Fonzo, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas at Austin

Must not be taking: Antidepressants, Antipsychotics, Lithium

Disqualifiers: Psychotic disorder, Bipolar, PTSD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 14

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach for individuals with treatment-resistant major depressive disorder, defined as not responding to at least two different antidepressants. Researchers are assessing the safety and feasibility of using psilocybin, a psychedelic compound, in combination with a brain stimulation technique called accelerated intermittent theta burst (aiTBS) rTMS to determine if this combination can more effectively treat depression. Participants will receive either a full or low dose of psilocybin with active or sham (placebo) aiTBS rTMS over several sessions. Individuals who have experienced depression for at least three months and have not responded to multiple antidepressant treatments may be suitable candidates for this study. As a Phase 2 trial, this research aims to evaluate the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to groundbreaking mental health research.

Will I have to stop taking my current medications?

Yes, if you are currently taking an antidepressant, antipsychotic, or other augmenting medication, you will need to stop taking them. There is a required taper-off period of 2-8 weeks, followed by a 2-5 week period without medications before the study starts, and you must remain off medications for about 6-8 weeks after the study begins.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that psilocybin, a substance found in certain mushrooms, is safe for humans. Most people handle it well, though some might feel temporarily anxious or confused. Studies have not reported any major safety concerns.

Similarly, researchers have tested accelerated intermittent theta burst (aiTBS) therapy, a type of brain stimulation, for safety. It is safe and well-tolerated for treating depression. Most people do not experience serious side effects, but mild headaches or scalp discomfort can occur.

Overall, previous research has shown both psilocybin and aiTBS therapy to be safe, with most side effects being mild and temporary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of psilocybin and accelerated intermittent theta burst (aiTBS) rTMS because it offers a novel approach to treating depression. Unlike standard antidepressants that often take weeks to show efficacy, psilocybin, a psychedelic compound, may produce rapid improvements in mood. Moreover, aiTBS rTMS, particularly in its accelerated form known as Stanford Neuromodulation Therapy (SNT) or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), provides a non-invasive brain stimulation technique that can enhance the effects of psilocybin. This innovative combination targets the brain in a unique way, potentially offering faster and more effective relief from depressive symptoms compared to existing treatments.

What evidence suggests that this trial's treatments could be effective for depression?

This trial will compare different treatment combinations for depression. Research has shown that psilocybin, a substance in certain mushrooms, can positively impact depression by affecting serotonin, a brain chemical that influences mood. Some participants in this trial will receive psilocybin, which studies have found to help reduce symptoms in people whose depression hasn't improved with other treatments.

Other participants will receive accelerated intermittent theta burst stimulation (aiTBS), a type of brain stimulation therapy that targets specific brain areas involved in mood control to lessen depressive symptoms. Both treatments offer hope for those whose depression hasn't improved with other therapies. ^{2 4 6 7 8}

Who Is on the Research Team?

Gregory A Fonzo, Ph.D.

Principal Investigator

The University of Texas at Austin

Are You a Good Fit for This Trial?

Adults aged 22-65 with treatment-resistant major depressive disorder, who have had at least two unsuccessful treatments for their current episode. Participants must be off certain medications before and during the trial, able to attend daily visits for about two weeks, and not have a history of psychotic disorders, substance abuse within the last year, or significant suicide risk recently.

Inclusion Criteria

You can understand and speak English well enough to follow instructions and talk to the study staff.

I am between 22 and 65 years old.

I am willing to stop my mental health meds for the study, with help and for a specific time.

Exclusion Criteria

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)

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

Head injury in the past two months, regardless of severity

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Baseline clinical and neurobiological assessments including fMRI and EEG recordings

1 day

1 visit (in-person)

Psilocybin Therapy

Participants undergo psychological preparation, psilocybin dosing, and integration sessions

5 days

5 visits (in-person)

SNT/SAINT Treatment

Participants receive active or sham SNT/SAINT treatment over 10 sessions daily for 5 consecutive days

5 days

5 visits (in-person)

Post-SNT Assessment

Post-SNT clinical and neurobiological assessments including fMRI and EEG recordings

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Multiple visits (in-person and virtual) at 1, 2, 3, 4, 6, 9, and 12 months

What Are the Treatments Tested in This Trial?

Interventions

• Accelerated intermittent theta burst (aiTBS) rTMS treatment
• Psilocybin

Trial Overview The study is testing if combining psilocybin therapy with an accelerated form of brain stimulation (aiTBS) is safe and works for people whose depression hasn't improved with other treatments. Some will get real aiTBS plus psilocybin while others will receive sham aiTBS (a fake version) with low-dose psilocybin.

How Is the Trial Designed?

Group I: Full dose COMP360 with active aiTBS rTMS Experimental Treatment 2 Interventions

25mg of COMP360 with the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) delivered over 10 sessions daily for 5 consecutive days.

Group II: Full dose COMP360 with sham aiTBS rTMS Active Control 2 Interventions

25mg of COMP360 with sham iTBS delivered over 10 sessions daily for 5 consecutive days.

Group III: Low dose comparator with active aiTBS rTMS Active Control 2 Interventions

1mg of COMP360 with the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) delivered over 10 sessions daily for 5 consecutive days.

Group IV: Low dose comparator with sham aiTBS rTMS Placebo Group 2 Interventions

1mg of COMP360 with with sham iTBS delivered over 10 sessions daily for 5 consecutive days.

Who Is Running the Clinical Trial?

University of Texas at Austin

Lead Sponsor

Trials

387

Recruited

86,100+

Published Research Related to This Trial

In a randomized controlled trial involving 56 patients with moderate to severe depression, bilateral theta-burst stimulation (TBS) and repetitive transcranial magnetic stimulation (rTMS) did not show significant improvements in depression scores compared to sham treatment.

However, there was a noted tendency for both active treatments to increase the responder rate, particularly for the TBS group, suggesting that further research may be needed to explore its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. Prasser, J., Schecklmann, M., Poeppl, TB., et al.[2015]

In a study of 54 patients with major depression, the combination of intermittent theta burst stimulation (iTBS) and low-frequency rTMS (LF-rTMS) significantly improved depression and anxiety symptoms more than high-frequency rTMS (HF-rTMS).

The results suggest that iTBS combined with LF-rTMS may be a promising alternative therapy for major depression, offering both efficacy and time-saving benefits compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study. Mi, Y., Ji, Y., Lou, Z., et al.[2022]

In a case series of 9 patients with major depressive disorder and bipolar disorder, accelerated theta-burst rTMS treatment over 8 days led to significant reductions in depression symptoms, as measured by the CES-D and CGI scales.

The treatment was well tolerated, with mild headaches being the most common side effect, and five patients achieving at least a 50% reduction in symptoms by the end of the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta-burst repetitive transcranial magnetic stimulation for depression in South Africa. Bröcker, E., van den Heuvel, L., Seedat, S.[2020]

In a phase II study involving 19 adults with treatment-resistant depression, a single 25 mg dose of synthetic psilocybin (COMP360) showed a significant reduction in depression scores, with a mean change of -14.9 on the MADRS scale after 3 weeks.

The treatment was generally safe, with 63.2% of participants experiencing mild treatment-emergent adverse events, but no serious adverse events or increased suicidal thoughts were reported, indicating a favorable safety profile for psilocybin in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Goodwin, GM., Croal, M., Feifel, D., et al.[2023]

Psilocybin treatment in depressed patients leads to transient increases in brain connectivity and activation in key neural areas, which are associated with positive antidepressant responses, suggesting a 'brain reset' effect.

The review analyzed 5 studies involving neuroimaging techniques, indicating that psilocybin-assisted psychotherapy may be particularly effective in both refractory and non-refractory depression cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurobiological Correlates of Psilocybin Response in Depression. Qasim, S., Zaheer, Z., Jawad, MY., et al.[2023]

In a study of 27 patients with moderate to severe major depressive disorder, psilocybin-assisted treatment showed significant and lasting antidepressant effects, with 75% of participants experiencing a treatment response and 58% achieving remission after 12 months.

There were no serious adverse events related to psilocybin, indicating a favorable safety profile, and participants reported meaningful personal and spiritual experiences that correlated with increased well-being, although these did not directly predict improvements in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Gukasyan, N., Davis, AK., Barrett, FS., et al.[2022]

A clinical trial involving 96 outpatients with moderate depression will investigate the effectiveness of intermittent theta burst stimulation (iTBS) on reducing depressive symptoms, comparing it to a sham treatment over ten sessions.

The study will also explore various factors, including genetic and neuropsychological measures, that may influence the response to iTBS, ensuring a thorough safety screening and adherence to ethical guidelines throughout the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. Ørbo, MC., Grønli, OK., Larsen, C., et al.[2023]

In a study involving 208 participants with treatment-resistant depression, both twice-daily and once-daily intermittent theta burst stimulation (iTBS) protocols showed improvements in depression scores, but there was no significant difference in efficacy between the two schedules after 10 and 30 days.

Response and remission rates were low in both treatment groups, indicating that neither protocol significantly accelerated the improvement of depressive symptoms in patients with treatment-resistant depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study. Blumberger, DM., Vila-Rodriguez, F., Wang, W., et al.[2022]

In a study involving 12 healthy adults, escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) were administered safely, with no serious adverse events reported, indicating a favorable safety profile for this psychedelic compound.

The pharmacokinetics of psilocin, the active metabolite of psilocybin, were linear across the tested doses, with an elimination half-life of about 3 hours, suggesting that no dose adjustments are necessary for individuals with mild to moderate renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Brown, RT., Nicholas, CR., Cozzi, NV., et al.[2022]

Psilocybin, a naturally occurring compound from certain fungi, has shown significant clinical efficacy in reducing symptoms of depression and anxiety in multiple clinical trials, indicating its potential as a treatment for psychiatric disorders.

There have been no significant adverse clinical events or recorded deaths associated with psilocybin use, suggesting it may be a safe option; however, larger studies are needed before it can be approved for widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Psilocybin in the Treatment of Psychiatric Disorders with Attention to Relative Safety Profile: A Systematic Review. Hodge, AT., Sukpraprut-Braaten, S., Narlesky, M., et al.[2023]

In a study of 60 patients with treatment-resistant unipolar depression, both intermittent theta burst stimulation (iTBS) and conventional 10 Hz rTMS showed similar efficacy in reducing depression scores and improving quality of life over a 6-month follow-up, with response rates of 36.7% for iTBS and 33.3% for rTMS.

iTBS is highlighted as a more time-efficient and cost-effective option compared to rTMS, suggesting it could be a valuable treatment alternative for patients with severe depression who have not responded to multiple antidepressant trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). Bulteau, S., Laurin, A., Pere, M., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34711062/

Stanford Neuromodulation Therapy (SNT): A Double-Blind ... SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression.

2. med.stanford.edu med.stanford.edu/content/dam/sm/mooddisorders/documents/2022/Williams%20N%20SAINT.pdf

Stanford Accelerated Intelligent Neuromodulation Therapy A recently completed non-inferiority trial demonstrated that 600 pulses of iTBS (3 min protocol) is non-inferior to 3,0000 pulses of 10hz. rTMS (37 min protocol) ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05849402

Accelerated Intermittent Theta-Burst Stimulation (aiTBS) in ... The aim of this study is to assess the efficacy of aiTBS applied to the left dorsolateral prefrontal cortex (L-DLPFC) in reducing depressive symptoms in ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32252538/

Stanford Accelerated Intelligent Neuromodulation Therapy for ... SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed.

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.2019.19070720

Stanford Accelerated Intelligent Neuromodulation Therapy ... SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03240692

Study Details | NCT03240692 | Stanford Accelerated ... This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03068715

Study Details | NCT03068715 | Stanford Accelerated ... This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression.

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006322325013563

Efficacy and Safety of Accelerated Intermittent Theta-burst ... The a-iTBS group showed significantly greater improvements in anxiety and self-reported depression at all time points compared to the sham group ...