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