Psilocybin for Treatment-Resistant Depression

Inclusion Criteria:

• Adults ≥ 21 years of age at Screening

• Diagnosis of Major Depressive Disorder (MDD)

• Score of at least 12 (symptomatic depression) on administration of the MontgomeryAsberg Depression Rating Scale (MADRS)

• Score of at least a 3 on question 8 on the MADRS evaluating loss of interest andability to feel at both Screening and Baseline Visit 1

• The participant's Major depressive disorder meets the criteria for beingtreatment-resistant, defined as not experiencing a 50% improvement to two or moreantidepressant treatments for adequate duration (6 weeks minimum) within the currentepisode, as determined by the Antidepressant Treatment Response Questionnaire (Desseilles et al., 2011; Posternak et al., 2004)

• Sufficiently competent in English Language

• Currently under the care of a psychiatric practitioner (MD, DO, NP, PA) OR under theconsistent care of a clinician within the UCHealth/CUMedicine health system (forexample, primary care provider, neurologist, therapist). Participants engaged inadditional psychosocial treatments beyond seeing a psychiatric practitioner orregular therapist will be evaluated on a case by case basis.

• Right-handed

• Women of childbearing potential (WOCBP) must agree to practice an effective means ofbirth control throughout the duration of the study. A person of childbearingpotential is anyone born female who has experienced menarche and who has notundergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy,bilateral oophorectomy) or has not completed menopause. Menopause is definedclinically as 12 months of amenorrhea in a person over age 45 in the absence ofother biological, physiological, or pharmacological causes.

• Have an identified support person and agree to be accompanied home (or to anotherwise safe destination) by the support person, or another responsible party,following dosing

• Written informed consent obtained from participant and ability for subject to complywith the requirements of the study.

• Ability to abstain from caffeine and nicotine for 2 hours prior to fMRI scan visits

Exclusion Criteria:

• Unstable medical conditions or serious abnormalities of complete blood count,chemistries, or EKG that in the opinion of the study physician would preclude safeparticipation in the trial. Some examples include:

1. Congestive heart failure

2. Clinically significant arrhythmias (e.g. ventricular fibrillation, torsades) orclinically significant EKG abnormality (i.e. QTC interval > 450)

3. Recent acute myocardial infarction or evidence of ischemia

4. Malignant hypertension

5. Congenital long QT syndrome

6. Acute renal failure

7. Severe hepatic impairment

8. Respiratory failure

• Risk for hypertensive crisis defined as Screening, Baseline, and Medication Session (prior to dosing) Blood Pressure >140/90 mmHg.

• High resting heart rate defined as Screening, Baseline, and Medication Session (prior to dosing) heart of rate of >90 BPM

• Significant CNS pathology as determined by self-report and confirmed by a historyand physical examination and review of medical records. Current and historicalpsychiatric disorders will be determined by the MINI. Specific examples include:

1. Primary or secondary cerebral neoplasm

2. Epilepsy

3. History of stroke

4. Cerebral aneurysm

5. Dementia

6. Delirium h. Current or lifetime primary psychotic disorder, bipolar affective disorder,affective disorder with psychotic features. Some examples include: i. Schizophreniaspectrum disorders j. Schizoaffective disorder k. Bipolar I or Bipolar II disorderl. History of mania m. Major depressive disorder with psychotic features

• Family history of first-degree relative with psychotic or serious bipolar spectrumillnesses. Examples include first-degree relative with:

1. Schizophrenia spectrum disorders

2. Schizoaffective disorder

3. Bipolar I disorder with psychotic features

• High risk of adverse emotional or behavioral reaction based on investigator'sclinical evaluation. Examples include:

1. Agitation

2. Violent behavior

• Currently under the care of a psychiatric practitioner (MD, DO, NP, PA) OR under the
consistent care of a clinician within the UCHealth/CUMedicine health system (for
example, primary care provider, neurologist, therapist). Participants engaged in
additional psychosocial treatments beyond seeing a psychiatric practitioner or
regular therapist will be evaluated on a case by case basis.
 
• Right-handed
 
• Women of childbearing potential (WOCBP) must agree to practice an effective means of
birth control throughout the duration of the study. A person of childbearing
potential is anyone born female who has experienced menarche and who has not
undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy,
bilateral oophorectomy) or has not completed menopause. Menopause is defined
clinically as 12 months of amenorrhea in a person over age 45 in the absence of
other biological, physiological, or pharmacological causes.
 
• Have an identified support person and agree to be accompanied home (or to an
otherwise safe destination) by the support person, or another responsible party,
following dosing
 
• Written informed consent obtained from participant and ability for subject to comply
with the requirements of the study.
 
• Ability to abstain from caffeine and nicotine for 2 hours prior to fMRI scan visits
 
 Exclusion Criteria:
 
• Unstable medical conditions or serious abnormalities of complete blood count,
chemistries, or EKG that in the opinion of the study physician would preclude safe
participation in the trial. Some examples include:
 

1. Congestive heart failure
 
2. Clinically significant arrhythmias (e.g. ventricular fibrillation, torsades) or
clinically significant EKG abnormality (i.e. QTC interval > 450)
 
3. Recent acute myocardial infarction or evidence of ischemia
 
4. Malignant hypertension
 
5. Congenital long QT syndrome
 
6. Acute renal failure
 
7. Severe hepatic impairment
 
8. Respiratory failure
 

• Risk for hypertensive crisis defined as Screening, Baseline, and Medication Session
 (prior to dosing) Blood Pressure >140/90 mmHg.
 
• High resting heart rate defined as Screening, Baseline, and Medication Session
 (prior to dosing) heart of rate of >90 BPM
 
• Significant CNS pathology as determined by self-report and confirmed by a history
and physical examination and review of medical records. Current and historical
psychiatric disorders will be determined by the MINI. Specific examples include:
 

1. Primary or secondary cerebral neoplasm
 
2. Epilepsy
 
3. History of stroke
 
4. Cerebral aneurysm
 
5. Dementia
 
6. Delirium
 
h. Current or lifetime primary psychotic disorder, bipolar affective disorder,
affective disorder with psychotic features. Some examples include: i. Schizophrenia
spectrum disorders j. Schizoaffective disorder k. Bipolar I or Bipolar II disorder
l. History of mania m. Major depressive disorder with psychotic features
 

• Family history of first-degree relative with psychotic or serious bipolar spectrum
illnesses. Examples include first-degree relative with:
 

1. Schizophrenia spectrum disorders
 
2. Schizoaffective disorder
 
3. Bipolar I disorder with psychotic features
 

• High risk of adverse emotional or behavioral reaction based on investigator's
clinical evaluation. Examples include:
 

1. Agitation
 
2. Violent behavior

• Active SUDs evaluated by the MINI and defined as: DSM-5 criteria for moderate orsevere alcohol or drug use disorder (excluding caffeine and nicotine) within thepast year

• Extensive use of serotonergic hallucinogens (e.g. LSD, psilocybin) defined as:

1. Any use in the last 6 months

2. >25 lifetime uses

• History of hallucinogen persisting perception disorder (HPPD)

• Women who are pregnant, as indicated by a positive urine pregnancy test atScreening. Women who intend to become pregnant during the study or who are currentlynursing.

• History of severe suicide attempt requiring hospitalization in the past year

• Have any suicidal ideation or thoughts, in the opinion of the study physician or PI,that presents a serious risk of imminent suicidal or self-injurious behavior

• Use of drugs or dietary supplements that per the discretion of the study team, havea mechanism of action that would interfere with procedures of study or have anadverse interaction with the study drug. Examples include directagonists/antagonists of serotonin receptors such as those listed below. SelectiveSerotonin Re-uptake Inhibitors and Serotonin Norepinephrine Re-uptake Inhibitors areallowed at the discretion of the PI. Individuals need to be off all non-alloweddrugs for a period of 5 half-lives prior to the baseline visit.

1. Antipsychotics

2. Trazodone

3. Nefazodone

4. Cyproheptadine

5. Mirtazapine

6. Flibanserin

7. Tricyclic antidepressants

8. Monoamine oxidase inhibitors

9. Lithium

10. Efavirenz

11. Serotonergic dietary supplements including St. John's Wort, L-tryptophan and 5-Hydroxytryptophan (5-HTP)

• Psychiatric condition judged to be incompatible with establishment of rapport withtherapy team and/or safe exposure to psilocybin based on investigator's clinicalevaluation

• Have an allergy or intolerance to any of the materials contained in either drugproduct

• Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine,Benzodiazepines, Cocaine, Methamphetamine, MDMA, Methadone, Opiates (Morphine,Oxycodone), Phencyclidine (PCP).

1. Note: Prescribed benzodiazepine medications and non-benzodiazepine sleepingmedications will be allowed to continue through the study period forparticipants who have been on a stable dose of such a medicine for at least 6weeks prior to Screening, as determined during review of concomitantmedications.

2. Note: Participants using cannabis, including legal cannabis, for any purposesand who do not screen positive for a moderate to severe substance use disordermust agree to refrain from use beginning at Screening and through to the end ofthe study.

3. Note: Participants using prescribed psychostimulants (amphetamines andRitalin), must agree to refrain from use for five half-lives of the drug asconfirmed with a negative Baseline drug test, and through to the end of thestudy.

• Have any psychological or physical symptom, medication or other relevant findingprior to baseline visit based on the clinical judgment of the PI or relevantclinical study staff that would make a participant unsuitable for the study.

• Claustrophobia

• Lack of internet access

• Weight over 300 pounds

• Metal in body unsafe for MRI or conditions that would make MRI unsafe forparticipants (e.g. aneurysm clip, cardiac pacemaker, etc.).

• Known contraindication to the drugs clonidine, diazepam, or olanzapine including:

1. Hypersensitivity or allergy to clonidine, diazepam, or olanzapine

2. Myasthenia gravis

3. Severe respiratory insufficiency

4. Severe hepatic insufficiency

5. Acute narrow-angle glaucoma 23. History of valvular heart disease 24. Inabilityof the study team to obtain proper medical/psychiatric information (e.g.records from a current or previous clinician), that per the PI, would preventan adequate assessment of the patient's eligibility and ability to safelyparticipate in the study.