Inclusion Criteria:

• Participants must meet all the following criteria to be included in the trial:
• Age18 to 85 years.
• Participant has a diagnosis of MDD.
• Moderate to severe depression at Screening.
• Participants have been on a stable dose of antidepressant medication at an adequate dose in the last 4 weeks prior to Screening.
• Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI ≤40 kg/m2), inclusive, at Screening.
• Participants with well controlled hypertension.
• Participant is able to refrain from smoking during the dosing session.
• Participants must use a condom plus spermicide during the trial and for 12 weeks afterwards.

Participants of childbearing potential must agree to use a highly effective method of and 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 have been postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
• Participants have 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.
• Family history of schizophrenia, schizoaffective disorder, or bipolar disorder type 1 (first-degree relatives).
• Significant suicide risk within 12 months of Screening.
• Current or previous diagnosis of treatment-resistant MDD.
• 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 antidepressants, mirtazapine, trazodone, moclobemide, buspirone, or an antipsychotic or mood stabilizer.
• Clinically relevant history of abnormal physical health interfering with the trial (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.
• Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically relevant abnormal results for heart rate.
• Participants have a presence or relevant history of organic brain disorders.
• Participant is taking or has taken OTC doses of 5 hydroxytryptophan or St John's Wort within prior to trial medication administration.
• Strenuous exercise prior to each clinic visit.
• 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.
• Unwilling to consent to audio and video recording of psychological support and dosing sessions.