A Study of a Psilocybin Analog (CYB003) in Humans With Major Depressive Disorder

Eligibility Criteria

• * Aged 18 to 75 years inclusive, at Screening
• * Participant has a diagnosis of MDD (single or recurrent episode as defined by DSM-5 \[if single episode, duration of ≥4 weeks and ≤36 months\] 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, independently confirmed additional assessments
• * Participant has been on a stable dose of antidepressant medication for an adequate duration in the last 4 weeks prior to Screening and has had an inadequate response (less than 50% improvement), as judged by the Investigator and clinical interviews.
• * Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI \< or = 40 kg/m2), inclusive, at Screening.
• * Participants with well controlled hypertension and who have been on a stable dose of 1 (at most 2) antihypertensive medications for \> or = 4 weeks prior to Screening are permitted.
• * Participant is able to refrain from smoking 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. Confirmation may be noted in the form of email, telephone contact, or written report.
• * Participants capable of producing sperm must use a condom during the trial and for 12 weeks after their final dose of trial medication, if their partner is a person of childbearing potential. In addition, their partner of childbearing potential must use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) from first dosing until 12 weeks following final dosing.
• * 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 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.
• * Participants of non-childbearing potential who are or were capable of producing eggs (ova) must be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy, and 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.
• * 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.
• * 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 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, or an antipsychotic or mood stabilizer.
• * Participant report of (or if available in medical record) significantly repetitive exposure to psilocin, or any other psychedelics, such as ayahuasca, mescaline, lysergic acid diethylamide, peyote, or 3,4-methylenedioxymethamphetamine, or use of ketamine or esketamine.
• * 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).
• * Has hypothyroidism or hyperthyroidism, unless controlled on appropriate medication with no change in dosage for at least 3 months prior to Screening.
• * Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically relevant abnormal results for heart rate (resting supine heart rate \>100 beats per minute) or blood pressure (\[BP\] resting supine systolic BP \>140 mmHg or diastolic BP \>90 mmHg) at Screening.
• * QT interval corrected for heart rate using Fridericia's formula \> or = 450 msec for males and \>470 milliseconds for females at Screening, following triplicate electrocardiogram (ECG) readings.
• * Presence of clinically significant ECG abnormalities at the Screening Visit, as defined by Investigator judgment.
• * 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 any of the following medical conditions: 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).
• * Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase or total bilirubin levels ≥1.5 x the ULN at Screening. These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range, the participant may be included only if the Investigator considers that the previous finding will not introduce additional risk factors and will not interfere with interpretation of safety data.
• * Positive urine test for drugs of abuse or alcohol breath test at Screening or at Day 1 or Day 22 prior to dosing. A positive test for cannabinoids (e.g., marijuana) at Screening may not exclude a participant if after discussion with and evaluation by the Investigator, the participant agrees not to use any marijuana or other cannabinoid products during the trial, and if allowed to participate, the participant must test negative for cannabinoids on Day 1 and Day 22.
• * History of substance use disorder within the last year, or intake of \> or = 21 units of alcohol weekly, and the inability to refrain from alcohol use from 48 hours before Screening and each scheduled visit until discharge from the trial site. One unit is equivalent to a 285 mL glass of full-strength beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
• * Known sensitivity to psilocin and/or any excipients present in the formulation.
• * Use of a prescription medicine other than stable chronic dose of antidepressant medication(s) with the exception of those permitted during the trial or over-the-counter (OTC) medicines during the 45 days before dosing. The Investigator and trial team may review medication on a case-by-case basis to determine if its use would compromise participant safety or interfere with trial procedures or data interpretation in discussion with the Medical Monitor and/or Sponsor.
• * Participant is taking or has taken any drugs known to inhibit monoamine oxidase within 45 days prior to trial medication administration.
• * Participant is taking or has taken OTC doses of 5 hydroxytryptophan or St John's Wort within 45 days prior to trial medication administration.
• * Strenuous exercise within 48 hours prior to each clinic visit.
• * Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the trial as outlined in this protocol, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this trial.
• * Other eligibility considerations (i.e., participant personal circumstances, behavior, and/or any current problem that might interfere with participation or that is incompatible with establishment of rapport or safe exposure to psilocin), as judged by the Investigator.
• * The participant has participated in a clinical trial and has received a medication or a new chemical entity within 12 weeks prior to dosing of current trial medication.
• * Donation of blood or plasma within 4 weeks prior to first dosing and until 4 weeks after final dosing.
• * 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.