TRIPS - Treatment to Improve Depression and/or Anxiety Using Psilocybin-assisted Psychotherapy in Cancer Survivors

Inclusion Criteria:

1. Subjects must have solid or hematological malignancy that does not involve thebrain.

2. Documentation of current malignancy that was treated and the patient has no evidenceof disease in the previous 6 months

3. Age ≥ 18 years.

4. Have a DSM-V psychiatric diagnosis, as determined by the SCID (Structured ClinicalInterview for DSM), of one or more of the following Axis I psychiatric disordersthat is judged to have been precipitated by the psychological stress of the cancerdiagnosis: Generalized Anxiety Disorder; Acute Stress Disorder; Posttraumatic StressDisorder; Major Depressive Disorder, Dysthymic Disorder; Adjustment Disorder withAnxiety; Adjustment Disorder with Depressed Mood; Adjustment Disorder with MixedAnxiety and Depressed Mood; Adjustment Disorder with Disturbance of Conduct;Adjustment Disorder with Disturbance of Emotions and Conduct. Psychiatric diagnosesare determined by. an MD Anderson licensed healthcare provider with graduate-levelprofession training and clinical experience in psychotherapy, licensed to practiceindependently.

5. Have an ECOG performance status of 0, 1, or 2.

6. Must have no major cognitive impairment and be oriented to person, place, and time (e.g. mini mental exam).

7. Must demonstrate willingness to travel to MD Anderson Cancer center for alltreatment and follow-up sessions, as well as consent to complete all evaluationinstruments and assessments.

8. Agree to abstain from any nicotine products for at least 8 hours prior to fMRIperformance.

9. Refrain from any psychoactive drugs (including alcohol) for 48 hours prior topsilocybin sessions and must refrain from psychoactive drugs 12 hours afterpsilocybin sessions. Must consent to urine drug screen (UDS) which will be givenbefore receiving psilocybin. Participants with positive drug test will be retested (UDS) after 6 weeks and included if the repeated UDS is negative. Patient testedpositive for a prescribed substance are eligible. Patient failing on the 2nd test (UDS) will be excluded.

10. Must be free from any regularly scheduled psychotropic (antidepressant/anxiolyticclass) medications for a minimum of 2 weeks prior to study. Intermittent or PRN useof short-acting anxiolytics or and anti-nausea medications (e.g., ondansetron) maybe permitted as defined below in exclusionary criteria). Ondansetron could be takenbut must be stopped at least 24 hours before psilocybin administration.

11. Inhibitors of monoamine oxidase, UGT1A9, 1A10, and aldehyde or alcohol dehydrogenaseshould be discontinued 5 half-lives prior to active dose of psilocybin.

12. Eligible subjects will have a third-party transportation by a licenses driver (e.g.friend, family or a driver) after the psilocybin session is complete. If a driver isused, a friend or family member must accompany them in the vehicle home

13. Fluent in Englishria). Ondansetron could be taken but must be stopped at least 24hours before psilocybin administration.

Exclusion Criteria:

1. Clinically significant suicidality or high risk of completed suicide defined as: i. Answer 'Yes' to C-SSRS Suicidal Ideation items 4 or 5 within the last 2 months atScreening or 'since last visit' at Baseline ii. Report having had any C-SSRSSuicidal Behavior item within the past 12 months at Screening or 'since last visit'at Baseline, as defined by 'Yes' to any of the following on the C-SSRS: actualattempt, interrupted attempt, aborted attempt, or preparatory acts iii. Have anysuicidal ideation or thoughts, in the opinion of the study physician or PI, thatpresents a serious risk of suicidal or self injurious behavior

2. History of bipolar disorder, psychosis (including a history of schizophrenia).

3. Functionally limiting comorbid conditions such as second primary malignancies in CNSor chest, and history of total laryngectomy or total glossectomy precluding themfrom communicating.

4. The effects of psilocybin on the developing human fetus are unknown. For thisreason, pregnant women will be excluded (Urine test for screening), women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstaining from intercourse with the oppositesex) prior to study entry and for the duration of study participation. This includesall female patients, between the onset of menses (as early as 8 years of age) and 55years unless the patient presents with an applicable exclusionary factor which maybe one of the following:

• Postmenopausal (no menses in greater than or equal to 12 consecutive months).

• History of hysterectomy or bilateral salpingo-oophorectomy.

• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausalrange, who have received Whole Pelvic Radiation Therapy).

• History of bilateral tubal ligation or another surgical sterilizationprocedure. Approved methods of birth control are as follows: Hormonalcontraception (i.e. birth control pills, injection, implant, transdermal patch,vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy,Subject/Partner post vasectomy, Implantable or injectable contraceptives, andcondoms plus spermicide. Not engaging in sexual activity for the total durationof the trial and the drug washout period is an acceptable practice; howeverperiodic abstinence, the rhythm method, and the withdrawal method are notacceptable methods of birth control. Should a woman become pregnant or suspectshe is pregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately.

5. Persons with first-degree relatives who have schizophrenia or other psychoticdisorders, or bipolar I or II disorder diagnosed by a qualified mental healthprofessional.

6. Documentation of current malignancy that is being treated with palliative intent.

7. Vulnerable populations, including children and cognitively impaired patients, willnot be enrolled in this study.

8. Patients with brain metastases.

9. Risk for hypertensive crisis defined as Screening, Baseline, and Medication Session (day of dosing, prior to dosing) Blood Pressure >blood pressure >180/120mmHG, HR >110 bpm . Of note, we will repeat vital signs for subjects with high initialreading and average three readings to determine eligibility criteria in such casesto account for normal variability in vital sign and "white coat hypertension."

10. Unstable medical conditions or serious abnormalities of complete blood count,chemistries, or ECG that in the opinion of the study physician would preclude safeparticipation in the trial. Some examples include: i. Uncompensated congestive heart failure ii. Clinically significant arrhythmias (e.g., ventricular fibrillation, torsades) or clinically significant ECG abnormality (i.e., QTC interval > 450) iii. Recent acute myocardial infarction or evidence ofischemia iv. Malignant hypertension v. Congenital long QT syndrome vi. Acute renalfailure vii. Severe hepatic impairment viii. Respiratory failure

11. Significant central nervous system (CNS) pathology. Some examples include: i. Primary or secondary cerebral neoplasm on imaging ii. Epilepsy and any history ofseizure (regardless of if related to epilepsy) except for a one-time febrile seizurein childhood iii. History of stroke in the past 3 years iv. Untreated cerebralaneurysm v. Dementia vi. Ongoing delirium in which subjects would not have thecapacity to participate in the study.

12 a. High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation. Examples include: i. Agitation ii. Violent behavior b. Active substance use disorders (SUDs) defined as: DSM-5 criteria for moderate or severe alcohol or drug use disorder (excluding caffeine and nicotine) within the past year c. Extensive use of serotonergic hallucinogens (e.g., LSD, psilocybin) defined as: i. Any use in the last 12 months ii. >22 lifetime uses d. History of hallucinogen persisting perception disorder (HPPD) e. Concurrent Medications i. Antidepressants ii. Centrally-acting serotonergic agents (e.g., MAO inhibitors) iii. Antipsychotics (e.g., first and second generation) iv. Mood stabilizers (e.g., lithium, valproic acid) v. Aldehyde dehydrogenase inhibitors (e.g., disulfiram) vi. Significant inhibitors of UGT 1A0 or UGT 1A10 vii. serotonin-acting dietary supplements (such as 5-hydroxytryptophan or St. John's wort) viii. efavirenz f. Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, Benzodiazepines, Cocaine, Cannabis, Methamphetamine, MDMA, Methadone, Opiates (Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC).

i. Note: Prescribed opiate medications (e.g., cancer-related pain) will be allowed to continue through the study period for participants who have been on a stable dose of such medicine for at least 1 month prior to Screening, as determined during review of concomitant medications.

ii. Note: Prescribed benzodiazepine medications and nonbenzodiazepine sleeping medications will be allowed to continue through the study period for participants who have been on a stable dose of such a medicine for at least 6 weeks prior to Screening, as determined during review of concomitant medications.

iii. Note: Participants using cannabis, including legal cannabis, for any purposes must agree to refrain from use beginning at Screening, as confirmed with a negative Baseline drug test, and through to the end of the study.

iv. Note: Participants using prescribed psychostimulants (amphetamines and Ritalin), must agree to refrain from use 72 hours prior to dosing and until 12 hours after dosing.

g. Have a psychiatric condition judged to be incompatible with establishment of rapport with the study therapists or safe exposure to psilocybin.

h. Have any psychological or physical symptom, medication or other relevant finding prior to randomization, based on the clinical judgment of the PI or relevant clinical study staff that would make a participant unsuitable for the study.

i. Have an allergy or intolerance to any of the materials contained in the drug product.

j. Be enrolled in another clinical trial assessing intervention(s) for anxiety, depression, and/or existential distress (e.g., pharmacologic or psychotherapeutic interventions).

13. Patients with non-fMRI compatible implants will be eligible but will not have fMRI.