SPL026 With or Without SSRIs in Participants With MDD

Inclusion Criteria:

* MDD diagnosis
* Previously tried at least one approved method of treatment for their depression
* No monoamine oxidase-inhibitor class antidepressants for at least 3 months
* Deemed healthy on the basis of a clinical history, physical examination, ECG, vital signs, laboratory tests of blood and urine
* No psychedelic drug use in the 6 months before dosing until the end of the study
* Willing to follow the contraception requirements of the trial
* Willing to be contacted by email and video call, and have online access
* Able to give fully informed written consent
* Test Cohort only: currently on a stable dose of an unspecified single SSRI alone and not in combination with any other psychiatric medications, for at least 6 weeks prior to Screening with no intention of making any changes
* Control Cohort only: no antidepressant medication for 6 months before dosing

Exclusion Criteria:

* Substance use disorder
* Current or clinically relevant history of a psychotic disorder, or first-degree relatives with a clinically relevant history of a psychotic disorder
* Significant history of mania
* Significant risk of suicide
* Clinically relevant abnormal findings at the screening assessment
* Blood pressure, heart rate, or QTcF outside the acceptable ranges
* Acute or chronic illness (other than MDD) or infection
* Clinically relevant abnormal medical history or concurrent medical condition (other than MDD)
* Use of any serotonergic psychedelics within 6 months prior to dosing
* Patients of child-bearing potential who are pregnant or lactating, or who are sexually active and not using a reliable method of contraception
* History of a severe adverse reaction to any drug or sensitivity to serotonergic psychedelic drugs
* Use of over-the-counter or prescribed medication (excluding oral contraceptives, hormone replacement therapy and SSRIs \[Test Cohort only\]) within previous 28 day before dose of trial medication; or paracetamol or ibuprofen within 4 hours prior to dosing