Inclusion Criteria:
* Aged ≥ 21
* Diagnosis of Advanced Cancer defined as:
* Solid tumors to include stage 3 or 4, metastatic illness, or recurrent illness
* Hematologic malignancies to include, but not limited to, Stage 3 or 4 non-Hodgkins lymphoma, late-stage multiple myeloma or second-line therapy for multiple myeloma, and all forms of acute myeloid leukemia
* Functional Status defined as: Eastern Cooperative Oncology Group (ECOG) ≤2 and Palliative Performance Scale (PPS) ≥60%
* Clinically significant Anxiety defined as SIGH-A \>17 at Screening
* Have an identified support person: agree to be accompanied home (or to an otherwise safe destination) by the support person, or another responsible party, following dosing
* Participants of childbearing potential must agree to practice an effective means of birth control throughout the duration of the study. A person of childbearing potential is anyone assigned female or intersex at birth who has experienced menarche and who has not undergone surgical sterilization (e.g., 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.
Exclusion Criteria:
* Unstable medical conditions or serious abnormalities of complete blood count, chemistries, or ECG that in the opinion of the study physician would preclude safe participation in the trial. Some examples include:
* Congestive heart failure
* Clinically significant arrhythmias (e.g., ventricular fibrillation, torsades) or clinically significant ECG abnormality (i.e., QTC interval \> 450)
* Recent acute myocardial infarction or evidence of ischemia
* Malignant hypertension
* Congenital long QT syndrome
* Acute renal failure
* Severe hepatic impairment
* Respiratory failure
* Risk for hypertensive crisis defined as Screening, Baseline, and Medication Session (prior to dosing) Blood Pressure \>140/90 mmHg.
* Significant central nervous system (CNS) pathology. Some examples include:
* Primary or secondary cerebral neoplasm
* Epilepsy
* History of stroke
* Cerebral aneurysm
* Dementia
* Delirium
* Primary psychotic or affective psychotic disorders. Some examples include current or past DSM-5 criteria for:
* Schizophrenia spectrum disorders
* Schizoaffective disorder
* Bipolar I with psychotic features
* Major Depressive Disorder with psychotic features
* Family history of first-degree relative with psychotic or serious bipolar spectrum illness. Examples include first-degree relative with:
* Schizophrenia spectrum disorders
* Schizoaffective disorder
* Bipolar I with psychotic features
* High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation. Examples include:
* Agitation
* Violent behavior
* Active substance use disorders (SUDs) defined as: DSM-5 criteria for alcohol or drug use disorder (excluding caffeine and nicotine) within the past year
* Extensive use of serotonergic hallucinogens (e.g., LSD, psilocybin) defined as:
* Any use in the last 12 months
* \>25 lifetime uses
* Clinically significant suicidality or high risk of completed suicide defined as:
* Active suicidal behavior (interrupted or aborted attempt; preparatory acts) as assessed by Baseline Version of C-SSRS. If C-SSRS items are 4 or 5, participant is ineligible
* History of suicide attempt(s) within the past year
* Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, that presents a serious risk of suicidal or self-injurious behavior
* History of hallucinogen persisting perception disorder (HPPD)
* Cognitive impairment as defined by: Montreal Cognitive Assessment Test (MoCA) \< 23
* Concurrent Medications
* Antidepressants
* Centrally-acting serotonergic agents (e.g., MAO inhibitors)
* Antipsychotics (e.g., first and second generation)
* Mood stabilizers (e.g., lithium, valproic acid)
* Aldehyde dehydrogenase inhibitors (e.g., disulfiram)
* Significant inhibitors of UGT 1A0 or UGT 1A10
* Niacin. Note: If taking any supplement containing niacin, agrees to suspend use for at least five days prior to dosing and for the duration of the study
* Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, Benzodiazepines, Cocaine, Cannabis, Methamphetamine, MDMA, Methadone, Opiates (Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC).
* 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.
* Note: Prescribed benzodiazepine medications and non-benzodiazepine 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.
* 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.
* Note: Participants using prescribed psychostimulants (amphetamines and Ritalin), must agree to refrain from use two weeks prior to baseline visit, as confirmed with a negative Baseline drug test, and through to the end of the study.
* Have a psychiatric condition judged to be incompatible with establishment of rapport with the study therapists or safe exposure to psilocybin
* Participants who are pregnant, as indicated by a positive urine pregnancy test at Screening, Baseline, or prior to dosing on medication administration sessions. Participants who intend to become pregnant during the study or who are currently nursing.
* 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.
* Have an allergy or intolerance to any of the materials contained in either drug product
* Be enrolled in another clinical trial assessing intervention(s) for anxiety, depression, and/or existential distress (e.g., pharmacologic or psychotherapeutic interventions)
