Psilocybin Analog for Depression

(APPROACH Trial)

Recruiting at 27 trial locations

Overseen By Kimball Johnson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Cybin IRL Limited

Must be taking: Antidepressants

Must not be taking: MAOIs, Antipsychotics, Psychedelics, others

Disqualifiers: Schizophrenia, Bipolar, Suicide risk, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 5

Duration: 6 weeks

220 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to examine the efficacy, safety, and tolerability of CYB003 compared to matching placebo as adjunctive treatment in participants with MDD.

Do I have to stop taking my current medications for the trial?

Participants must be on a stable dose of a single antidepressant medication and cannot be taking certain medications like monoamine oxidase inhibitors, tricyclic antidepressants, or antipsychotics. The protocol does not specify a washout period, but you may need to adjust your current medications to meet the trial's requirements.

What data supports the effectiveness of the drug CYB003 for depression?

Research shows that psilocybin, a component similar to CYB003, has been effective in reducing symptoms of depression, including treatment-resistant depression, in several clinical trials. These studies found that psilocybin can have rapid and lasting antidepressant effects from just one or two doses. ^{1 2 3 4 5}

Is the psilocybin analog safe for humans?

Initial studies on psilocybin, a similar compound, have shown basic safety in both healthy volunteers and people with treatment-resistant depression, with no signs of addiction potential. ^{3 5 6 7 8}

How does the drug psilocybin analog differ from other depression treatments?

Psilocybin analog is unique because it acts rapidly and involves a single dose that targets serotonin receptors, particularly the 5-HT2A receptors, which may lead to changes in brain connectivity and structure. Unlike traditional antidepressants, it may not require daily dosing and can be used alongside existing medications like SSRIs, offering a novel approach for treatment-resistant depression. ^{9 10 11 12 13}

Research Team

Felix Mazer

Principal Investigator

Cybin IRL Limited

Eligibility Criteria

This trial is for adults aged 18-75 with moderate to severe Major Depressive Disorder (MDD) who haven't had enough improvement from their current antidepressants. They must be non-smokers during sessions, have a stable BMI of 40 or less, and if they can have children, agree to use effective contraception.

Inclusion Criteria

I can avoid smoking for up to 8 hours during treatment.

I've been on the same antidepressant for the last 4 weeks with less than 50% improvement.

I am between 18 and 75 years old.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

1 visit (in-person)

Treatment

Participants receive CYB003 or placebo in 2 dosing sessions, approximately three weeks apart, while continuing on their current antidepressants and receiving psychological support

6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Extension

Non-responders may receive CYB003 in a subsequent extension trial

Treatment Details

Interventions

• CYB003

Trial Overview The study tests CYB003's effectiveness and safety as an additional treatment for MDD against a placebo. Participants will also receive psychological support. The goal is to see if CYB003 helps improve depression symptoms more than the placebo.

Participant Groups

Group I: Experimental Arm A: CYB003 in 2 of 2 Dosing Sessions Experimental Treatment 2 Interventions

Arm A participants will receive 16 mg of CYB003 in 2 of 2 medicine sessions, approximately three weeks apart. All Arm A participants will continue on their current antidepressants and receive psychological support throughout the study.

Group II: Placebo Comparator Arm B: Placebo in 2 of 2 Dosing Sessions Placebo Group 2 Interventions

Arm B participants will receive placebo in 2 of 2 Dosing Sessions, approximately three weeks apart. All Arm B participants will continue on their current antidepressants and receive psychological support throughout the study. Non-responders will be eligible to receive CYB003 in a subsequent extension trial.

Who Is Running the Clinical Trial?

Cybin IRL Limited

Lead Sponsor

Trials

5

Recruited

860+

Worldwide Clinical Trials

Collaborator

Trials

70

Recruited

15,800+

Findings from Research

In a phase 2 clinical trial involving 233 participants with treatment-resistant depression, a single dose of 25 mg of COMP360 (synthetic psilocybin) significantly improved depression severity, anxiety, and overall functioning compared to a 1 mg control dose.

The 10 mg dose also showed some benefits, but the 25 mg dose was more effective across all measured outcomes, highlighting the potential of psilocybin as a treatment option for individuals with severe depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. Goodwin, GM., Aaronson, ST., Alvarez, O., et al.[2023]

A systematic review and meta-analysis of seven studies involving 489 participants identified optimal dosages of psilocybin for reducing depression scores, with effective doses of 8.92 mg for secondary depression, 24.68 mg for primary depression, and 36.08 mg for both groups combined.

The study found significant dose-response relationships for both efficacy and side effects, indicating that while higher doses may be more effective, they also increase the risk of adverse effects like nausea and prolonged psychosis, highlighting the need for careful dosage management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies. Perez, N., Langlest, F., Mallet, L., et al.[2023]

Psilocybin has been rigorously tested in a randomized trial for its safety and efficacy in treating treatment-resistant depression, confirming its positive effects seen in previous studies.

The paper discusses psilocybin's mechanism of action and highlights its relative safety and lack of addiction potential, suggesting it could be a promising option for larger trials aimed at establishing its risk-benefit ratio in depression treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Return of the psychedelics: Psilocybin for treatment resistant depression. Patra, S.[2017]

In a placebo-controlled study involving individuals with moderate to severe major depressive disorder, psilocybin (0.3 mg/kg) showed larger antidepressant effect sizes compared to placebo, with 66.7% of participants responding and 46.7% achieving remission after treatment.

The antidepressant effects of psilocybin persisted for an average of 2 months, indicating its potential as a long-lasting treatment option for depression, although the strength of the mystical experience during dosing did not correlate with these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Sloshower, J., Skosnik, PD., Safi-Aghdam, H., et al.[2023]

Psilocybin has shown promise in clinical trials for reducing symptoms of depression, indicating its potential as a novel treatment option.

Patients with treatment-resistant depression (TRD) may benefit the most from psilocybin therapy, although the risks associated with its use are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. Kozak, Z., Johnson, MW., Aaronson, ST.[2023]

A single, moderate dose of psilocybin significantly reduced depressive symptoms in 52 participants with major depressive disorder, showing a decrease of 13.0 points on the MADRS scale compared to baseline, which was significantly greater than the placebo group.

54% of participants in the psilocybin group met the criteria for remission of depression 14 days after treatment, and no serious adverse events were reported, indicating a favorable safety profile for this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. von Rotz, R., Schindowski, EM., Jungwirth, J., et al.[2023]

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 psychedelic drug, shows promising safety and efficacy in treating major depression and treatment-resistant depression (TRD), with initial phase 2 trials indicating positive outcomes when combined with psychological support.

The first international randomized controlled trial in 2022 found that a 25 mg dose of psilocybin was effective compared to an active placebo, and phase 3 trials are set to begin in 2023, suggesting a growing interest in psilocybin as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development of psilocybin therapy for treatment-resistant depression: an update. Borissova, A., Rucker, JJ.[2023]

Psilocybin, a naturally occurring compound found in certain mushrooms, shows promise as a rapid-acting antidepressant, particularly for individuals with treatment-resistant depression, by acting on serotonin receptors, especially the 5-HT2A receptor.

The antidepressant effects of psilocybin are believed to involve not only serotonin modulation but also changes in neural circuitry and brain regions associated with depression, suggesting a complex mechanism of action that could lead to new treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression. Ling, S., Ceban, F., Lui, LMW., et al.[2022]

Psilocybin has been identified as a rapidly acting antidepressant that may have long-lasting effects, suggesting its potential as a treatment for depression.

Research by Shao et al. (2021) indicates that psilocybin promotes the formation of dendritic spines in cortical layer V pyramidal neurons, which may explain its therapeutic benefits at the cellular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cranial windows of perception. DiBerto, JF., Roth, BL.[2022]

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 shows potential as a treatment for depression, with evidence suggesting it may work through changes in serotonin and glutamate receptor activity, as well as promoting synaptogenesis, based on a review of 14 studies.

The review highlights that psilocybin may alter brain activity, particularly in areas like the hippocampus and prefrontal cortex, but the exact mechanisms remain unclear, indicating a need for further research to understand how it alleviates depressive symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin's Potential Mechanisms in the Treatment of Depression: A Systematic Review. Lee, HJ., Tsang, VW., Chai, BS., et al.[2023]

A single 25 mg dose of psilocybin has shown short-term antidepressant effects in individuals with medication-resistant depression, suggesting it may be a promising treatment option.

Further research is needed to understand the relationship between psilocybin's psychedelic effects and its antidepressant benefits, as well as to assess potential risks, including suicide risk associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is psilocybin an effective antidepressant and what is its Mechanism of action? Mann, JJ.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Return of the psychedelics: Psilocybin for treatment resistant depression. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]

8. England pubmed.ncbi.nlm.nih.gov

The development of psilocybin therapy for treatment-resistant depression: an update. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

The cranial windows of perception. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Psilocybin's Potential Mechanisms in the Treatment of Depression: A Systematic Review. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Is psilocybin an effective antidepressant and what is its Mechanism of action? [2023]