"A Study of a Deuterated Psilocin Analog (CYB003) in Humans With Major Depressive Disorder" (APPROACH)

A Phase III, Placebo-Controlled, Randomized, Double-Blind Trial of Oral Doses of CYB003 to Assess Combined Safety and Efficacy in Humans With Major Depressive Disorder

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Placebo; Behavioral: Psychological Support; Drug: CYB003

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85022
      • Scottsdale Research Institute
    • Phoenix, Arizona, United States, 85050
      • Mountain Clinical Trials
    • Tucson, Arizona, United States, 85704
      • Noble Clinical Research
    • Tucson, Arizona, United States, 85715
      • Del Sol Research Management
  • California
    • Bellflower, California, United States, 90706
      • CenExel CIT (Clinical Innovations, Inc)
    • La Jolla, California, United States, 92037
      • Kadima Neuropsychiatry Institute
    • Los Angeles, California, United States, 90025
      • Bespoke Treatment/Lipov Medical Group
    • Montclair, California, United States, 91763
      • Catalina Research Institute
    • Oceanside, California, United States, 92056
      • Excell Research, Inc
    • San Francisco, California, United States, 94114
      • Open Mind Therapeutics
    • San Juan Capistrano, California, United States, 92675
      • Inland Psychiatric Medical Group Inc
  • Colorado
    • Denver, Colorado, United States, 80209
      • Mountain View Clinical Research
    • Evergreen, Colorado, United States, 80439
      • Starlight Clinical Research
  • Florida
    • Hollywood, Florida, United States, 33024
      • Research Centers of America
    • Maitland, Florida, United States, 32751
      • K2 Medical Research-Maitland
    • Miami, Florida, United States, 33135
      • Floridian Neuroscience Institute
    • North Miami, Florida, United States, 33161
      • Segal Trials West Broward
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc
    • Orlando, Florida, United States, 32807
      • Combined Research Orlando Phase I-IV
    • Orlando, Florida, United States, 32803
      • Charter Research
    • Tampa, Florida, United States, 33634
      • K2 Medical Research - Tampa
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research, CenExel
    • Decatur, Georgia, United States, 30330
      • CenExel iResearch Atlanta
    • Savannah, Georgia, United States, 31405
      • CenExel iResearch Savannah
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Uptown Research Institute
    • Chicago, Illinois, United States, 60640
      • Great Lakes Clinical Trials, DBA Flourish Research
    • Skokie, Illinois, United States, 60076
      • Psychiatric Medicine Associates, LLC
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • DelRicht Research
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Sunstone Medical, PC
  • Massachusetts
    • Boston, Massachusetts, United States, 02116
      • Adams Clinical Boston
    • Boston, Massachusetts, United States, 02472
      • Adams Clinical
    • Springfield, Massachusetts, United States, 01103
      • Elixia Health
  • Nevada
    • Las Vegas, Nevada, United States, 89121
      • Oasis Clinical Trials
    • Las Vegas, Nevada, United States, 89119
      • Redbird Research, LLC
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes, Princeton Medical Institute
  • New York
    • New York, New York, United States, 100029
      • Adams Clinical Harlem
    • The Bronx, New York, United States, 10461
      • Adams Clinical Bronx
  • North Carolina
    • Monroe, North Carolina, United States, 28112
      • Monroe Biomedical Research
  • Ohio
    • North Canton, Ohio, United States, 44720
      • Neurobehavioral Clinical Research
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Adams Clinical Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Clinical Neuroscience Solutions, CNS Healthcare
  • Texas
    • DeSota, Texas, United States, 75115
      • InSite Clinical Research, LLC
    • Houston, Texas, United States, 77433
      • Zillan Clinical Research
  • Utah
    • Murray, Utah, United States, 84107
      • Cedar Clinical Research
    • Orem, Utah, United States, 84058
      • Inner Space Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet all the following criteria to be included in the trial:

• Aged 18 to 85 years inclusive, at Screening
• Participant has a diagnosis of MDD (single or recurrent episode as defined by DSM-5 TR [if single episode, duration of ≥4 weeks and ≤24 months] and established as per evaluation by the Investigator. The first MDD episode must have occurred prior to age 60.
• Depression is of moderate to severe degree at Screening and Baseline, independently confirmed by additional clinical assessments
• Participant has been on a stable dose of a single antidepressant medication at an adequate dose (label specified) for an adequate duration in the last month prior to Screening and has had an inadequate response (less than 50% improvement), as judged by the Investigator.
• Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI ≤ 40 kg/m2), inclusive, at Screening.
• Participant is able to refrain from nicotine use during the dosing session (up to 8 hours)
• Registered with a healthcare professional who can confirm the diagnosis and previous treatments received by the participant.
• Participants capable of producing sperm must use a condom plus spermicide during the trial and for 12 weeks after their final dose of trial medication, if their partner is a person of childbearing potential.
• Participants of childbearing potential who have a partner capable of producing sperm must agree to use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) in combination with the use of a condom plus spermicide during the trial and for 12 weeks after their final dose of trial medication. Such participants must have a negative pregnancy test at Screening and Day 1 prior to dosing.
• Female participants who were capable of producing eggs (ova) must agree that the only exclusion from the requirement for contraception during the trial is to be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle-stimulating hormone level in the menopausal range, unless the participant is taking hormone replacement therapy or is using hormonal contraception.
• Participant has provided written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.

Exclusion Criteria:

Participants with any of the following characteristics/conditions will be excluded from trial participation:

• Current or previously diagnosed schizophrenia spectrum or other psychotic disorders, including schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder, brief psychotic disorder, current or previous history of bipolar disorder, or current borderline personality disorder.
• Participants with a medical diagnosis of attention deficit hyperactivity disorder (ADHD) will be excluded if currently taking medication for ADHD
• Family history of schizophrenia, schizoaffective disorder, or bipolar disorder type 1 (first degree relatives).
• Significant suicide risk within the past 6 months, during the Screening Period, or at Baseline; or (b) suicidal behaviors within 12 months of Screening; or (c) clinical assessment of significant suicidal risk during clinical interview; or (d) non-suicidal self-injury within 12 months of Screening.
• Current or previous diagnosis of treatment-resistant MDD, defined as failure to respond to 2 or more antidepressant treatments of 2 different classes given at an adequate dose (label specified) for an adequate duration as judged by the Investigator and clinical interview.
• Has had electroconvulsive treatment, transcranial magnetic stimulation, deep brain stimulation, or vagal nerve stimulation for any episode of MDD in the last 6 months.
• Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, mirtazapine, trazodone, moclobemide, buspirone, ketamine or S-ketamine, or an antipsychotic or mood stabilizer for MDD. Note: if receiving these medications for another indication, they must be discontinued ≥ 14 days or 5 half-lives, whichever is longer, prior to Day 1.
• Participant report of (or if available in medical record) exposure to psilocin, or 5-HT2a receptor agonists, or any other psychedelics, such as ayahuasca, mescaline, lysergic acid diethylamide, peyote, or 3,4-methylenedioxymethamphetamine, more than 10 times over the participant's lifetime or any psychedelic use within 12 months prior to Screening.
• Participant report of (or if available in medical record) treatment with ketamine or S-ketamine use within 6 months prior to Screening.
• Clinically relevant history of abnormal physical health interfering with the trial as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including but not limited to, neurological, cardiovascular, respiratory, gastrointestinal [including dyspepsia or gastroesophageal reflux disease], hepatic, or renal disorder).
• Participants with renal insufficiency.
• Has hypothyroidism or hyperthyroidism, unless controlled on appropriate medication.
• Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically relevant abnormal results for heart rate or blood pressure
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism, or excretion of the trial medication.
• Participant has a presence or relevant history of organic brain disorders (e.g., epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumor or other medical conditions associated with seizures or convulsions).
• Known sensitivity to psilocin and/or any excipients present in the formulation.
• Participant is taking or has taken OTC doses of 5-HTP or St John's Wort within 14 days prior to trial medication administration.
• The participant has participated in a clinical trial and has received a medication or a new chemical entity within 12 weeks prior to dosing with the current trial medication. Participants who have completed observational or non-interventional studies will be allowed.
• Participants capable of producing sperm who will not abstain from sperm donation between first dosing and 12 weeks after final dosing.
• Participants of childbearing potential who are pregnant, breastfeeding, planning to conceive or unwilling to abstain from egg (ova) donation between first dosing and 12 weeks after final dosing.
• History of serotonin syndrome.
• Unwilling to consent to audio and video recording of psychological support and dosing sessions.
• Staff and family members of Cybin IRL Limited, investigator sites, contract research organization or other vendors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm A: CYB003 in 2 of 2 Dosing Sessions; 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.	Behavioral: Psychological Support; Manualized psychological support performed by facilitators; Drug: CYB003; CYB003 is a Deuterated Psilocin Analog.
Placebo Comparator: Placebo Comparator Arm B: Placebo in 2 of 2 Dosing Sessions; 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.	Drug: Placebo; Placebo; Behavioral: Psychological Support; Manualized psychological support performed by facilitators

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Åsberg Depression Rating Scale (MADRS)	The MADRS is a 10-item scale with ratings based on a clinical interview which moves from broadly phrased questions about symptoms to more detailed ones allowing a precise rating of severity.	Screening Day-45, Baseline Day-1, Day 2, Day 10, Day 21, Day 23, Day 31, and Day 42 (End of Treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Beck Depression Inventory-Second Edition (BDI-II)	The Beck Depression Inventory-Second Edition (BDI-II) is a 21-question multiple-choice self-report inventory, assessing depressive symptoms and severity.	Baseline Day-1, Day 21, and Day 42 (End of Treatment)
The Clinical Global Impression Scale (CGI-S)	The Clinical Global Impression Scale is a clinician-rated instrument comprised of 3 global measures: severity of illness, global improvement, and efficacy index. Only the severity of illness and global improvement measures will be utilized for this trial.	Screening Day-45, Baseline Day-1, and Day 42 (End of Treatment)
The Generalized Anxiety Disorder 7-item scale (GAD-7)	The Generalized Anxiety Disorder 7-item scale (GAD-7) is a 7-item self-reported assessment that measures the severity of generalized anxiety disorder symptoms.	Baseline Day-1, Day 21, and Day 42 (End of Treatment)
The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)	The original Quality of Life Enjoyment and Satisfaction Questionnaire is a 93 item, participant facing, self-reported measure used to evaluate intervention-related changes in quality of life, divided into the following sections: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) version will be used in this trial.	Baseline Day-1, Day 21, and Day 42 (End of Treatment)

Collaborators and Investigators

• Sponsor: Cybin IRL Limited
• Collaborators: Worldwide Clinical Trials
• Investigators: Study Chair: Clinical Development, Cybin IRL Limited

Publications and helpful links

Helpful Links

• Apply for Trial Here

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: August 20, 2024
• First Submitted That Met QC Criteria: August 20, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): August 12, 2026
• Last Update Submitted That Met QC Criteria: August 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Depression; MDD; Major Depressive Disorder; Psilocybin; Psychedelic; Psilocin; CYB003; CYB003-001
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: CYB003-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No