Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients - Proof of Concept

Inclusion Criteria: * Capable of giving informed consent * Informed consent as documented by signature * Male and female in- and outpatients 18 years to 60 years of age * Right-handedness * DSM-IV-diagnosis of mild or moderate major depressive episode without psychotic features (based on clinical assessment and confirmed by the SCID Interview) * Score of ≥ 10 and ≤40 on the Montgomery-Asberg Depression Rating Scale (MADRS) at both screening and baseline visits. * Drug free from any psychotropic medication for at least two weeks (or five weeks for fluoxetine) before enrolling in the study * Judged clinically not to be a serious suicide risk * Good physical health with no unstable medical conditions, as determined by medical history, physical examination, routine blood labs, electrocardiogram, urineanalysis, and urine toxicology * Normal level of language comprehension and German or Swiss-German as first language * Willing to refrain from drinking alcohol the day before testing days, from drinking alcohol and caffeinated drinks during the testing days and from consuming psychoactive substances 2 weeks before enrolling in the study and for the remainder of the study * Women of childbearing potential must be using an effective, established method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices. Note: female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential. * Have a family member or friend who can pick them up and stay with them overnight after the psilocybin administration sessions (driving is forbidden at drug treatment days) Exclusion Criteria: * Lifetime history of bipolar disorder (I, II, not otherwise specified) * Lifetime history of schizophrenia, schizoaffective disorder, or psychosis not otherwise specified * History of DSM-IV drug or alcohol dependence or abuse (except for caffeine or nicotine) within three months prior to enrollment * Comorbid Axis I anxiety disorder diagnoses will be permitted if they do not require current treatment * Family history of schizophrenia or schizoaffective disorder, or bipolar disorder type 1 (first or second degree relatives) * Lifetime history of hallucinogen use on more than 10 occasions * Getting psychotherapeutic or psychological treatment from third parties during the study is forbidden * Abnormal electrocardiogram * Any unstable illness as determined by history or laboratory tests * BMI \<17 or \>35 * Uncorrected hypo- or hyperthyroidism * Women who are pregnant or breast feeding, or have the intention to become pregnant during the course of the study * Contraindications to magnetic resonance imaging (MRI safety form) * During the study, new use or dose changes of already existing concomitant medication without prior informing the investigators is forbidden * Allergy, hypersensitivity, or other adverse reaction to previous use of psilocybin or other hallucinogens * High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support) * Participation in another study with investigational drug within the 30 days preceding and during the present study