Psilocybin-Assisted Psychotherapy in Patients With Advanced Cancer on Maintenance Therapy

Inclusion Criteria:

1. Participants must have one of the following histology documented tumor types:non-small cell lung carcinoma, renal cell carcinoma, urothelial carcinoma, prostatecancer, head and neck squamous cell carcinoma, ovarian cancer, breast cancer,gastric/GEJ cancer, cervical, anal, or MSI-high

2. Documentation of locally advanced, recurrent, or metastatic incurable malignancythat has partially responded or progressed after at least 1 available standardtherapy and disease is stable (no progression of disease for 3 months or more oncurrent treatment regimen)

3. No prior grade 3 AEs on current standard of care cancer treatment regimen;

4. Age ≥ 25 years; as by the age of 25 brain is fully developed.

5. Have a DSM-V psychiatric diagnosis, as determined by the SCID (Structured ClinicalInterview for DSM, by a board certified psychiatrist), of one or more of thefollowing Axis I psychiatric disorders that is judged to have been precipitated bythe psychological stress of the cancer diagnosis: Generalized Anxiety Disorder;Acute Stress Disorder; Posttraumatic Stress Disorder; Major Depressive Disorder;Dysthymic Disorder; Adjustment Disorder with Anxiety; Adjustment Disorder withDepressed Mood; Adjustment Disorder with Mixed Anxiety and Depressed Mood;Adjustment Disorder with Disturbance of Conduct; Adjustment Disorder withDisturbance of Emotions and Conduct. Psychiatric diagnosis are determined by a MDAnderson board certified psychiatrist.

6. At least 6 months life expectancy as per primary medical oncologist.

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

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

9. 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.

10. Agree to abstain from any nicotine products for at least 12 hours prior topsilocybin administration until approximately 12 hours after (or when allpost-session questionnaires have been completed) as well as on days of salivarysample collection.

11. Refrain from any psychoactive drugs (including alcohol) for 48 hours prior topsilocybin sessions (except as described above for nicotine and caffeine) and mustrefrain from psychoactive drugs 12 hours after psilocybin sessions. Must consent tourine drug screen (UDS) which will be given before receiving psilocybin.Participants with positive drug test will be retested (UDS) after 6 weeks andincluded if the repeated UDS is negative. Participant tested positive for aprescribed substance are eligible. Participant failing on the 2nd test (UDS) will beexcluded.

12. Must be free from any regularly scheduled psychotropic (antidepressant/anxiolyticclass) medications and those with primary MOA on serotonergic neurons (e.g.,ondansetron) for a minimum of 2 weeks prior to study or 4 weeks for SSRI.Intermittent or PRN use of short-acting anxiolytics may be permitted as definedbelow in exclusionary criteria).

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

14. Eligible participants will have a responsible individual that will providetransportation home after the psilocybin session is complete.

15. Fluent in English

Exclusion Criteria:

1. History of depression prior to cancer diagnosis.

2. 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

3. History of bipolar disorder, psychosis (of any nature), and seizures.

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

5. ECG with QTc > 450.

6. Patients with metal implants.

7. Asymptomatic ALT or AST elevations >/= 5X upper limit of normal, symptomatic ALT orAST elevations >/= 2X upper limit of normal, or total bilirubin >/= 2X upper limitof normal.

8. 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; abstinence) prior to study entry and for theduration of study participation. This includes all female participants, between theonset of menses (as early as 8 years of age) and 55 years unless the participantpresents with an applicable exclusionary factor which may be 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 menopausal range, who have receivedWhole Pelvic Radiation Therapy). History of bilateral tubal ligation or another surgical sterilization procedure. Approved methods of birth control are as follows: Hormonal contraception (i.e. birthcontrol pills, injection, implant, transdermal patch, vaginal ring), Intrauterinedevice (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy,Implantable or injectable contraceptives, and condoms plus spermicide. Not engagingin sexual activity for the total duration of the trial and the drug washout periodis an acceptable practice; however periodic abstinence, the rhythm method, and thewithdrawal method are not acceptable methods of birth control. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately.

9. persons with first- or second-degree relatives who have schizophrenia or otherpsychotic disorders, or bipolar I or II disorder.

10. Actively progressing disease as defined by the primary oncologist.

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

12. Participants with brain metastases.

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

14. 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

15. Significant central nervous system (CNS) pathology. Some examples include: i. Primary or secondary cerebral neoplasm ii. Epilepsy iii. History of stroke iv.Cerebral aneurysm v. Dementia vi. Delirium

16. a. High risk of adverse emotional or behavioral reaction based on investigator'sclinical evaluation. Examples include: i. Agitation ii. Violent behavior b. Activesubstance use disorders (SUDs) defined as: DSM-5 criteria for moderate or severealcohol or drug use disorder (excluding caffeine and nicotine) within the past yearc. Extensive use of serotonergic hallucinogens (e.g., LSD, psilocybin) defined as:i. Any use in the last 12 months ii. >25 lifetime uses d. History of hallucinogenpersisting perception disorder (HPPD) e. Concurrent Medications i. Antidepressantsii. Centrally-acting serotonergic agents (e.g., MAO inhibitors) iii. Antipsychotics (e.g., first and second generation) iv. Mood stabilizers (e.g., lithium, valproicacid) v. Aldehyde dehydrogenase inhibitors (e.g., disulfiram) vi. Significantinhibitors of UGT 1A0 or UGT 1A10 vii. Niacin. Note: If taking any supplementcontaining niacin, agrees to suspend use for at least five days prior to dosing andfor the duration of the study f. Have a positive urine drug test includingAmphetamines, 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 allowedto continue through the study period for participants who have been on a stable doseof such medicine for at least 1 month prior to Screening, as determined duringreview of concomitant medications. ii. Note: Prescribed benzodiazepine medications and nonbenzodiazepine sleepingmedications will be allowed to continue through the study period for participantswho have been on a stable dose of such a medicine for at least 6 weeks prior toScreening, as determined during review of concomitant medications. iii. Note: Participants using cannabis, including legal cannabis, for any purposesmust agree to refrain from use beginning at Screening, as confirmed with a negativeBaseline 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 two weeks prior to baseline visit, as confirmed witha negative Baseline drug test, and through to the end of the study. g. Have a psychiatric condition judged to be incompatible with establishment ofrapport with the study therapists or safe exposure to psilocybin h. Have anypsychological or physical symptom, medication or other relevant finding prior torandomization, based on the clinical judgment of the PI or relevant clinical studystaff that would make a participant unsuitable for the study. i. Have an allergy or intolerance to any of the materials contained in either drugproduct j. Be enrolled in another clinical trial assessing intervention(s) foranxiety, depression, and/or existential distress (e.g., pharmacologic orpsychotherapeutic interventions)

17. Participants who have any of the below niacin contraindications:

18. Active liver disease or unexplained persistent elevations in hepatictransaminases

19. active peptic ulcer disease

20. arterial bleeding

21. Hypersensitivity to niacin or any component of this medication

22. BP> 200/110 (or malignant hypertension defined as 200/120) would prevent a patientfrom receiving psilocybin dosing and would prompt calling a physician during bloodpressure monitoring for cardiac risk evaluation.