Exploring the Safety, Acceptability, and Efficacy of Psilocybin Among Non-Small Cell Lung Cancer Patients With Major Depressive Disorder: A Proof-of-Concept Trial (DREAM LUNG STUDY)

Inclusion Criteria: * Individuals diagnosed with NSCLC, confirmed by pathology report * Have a Karnofsky performance status \>= 60 * Participants receiving chemotherapy, radiation therapy, and biologic therapies may participate while receiving those therapies if they are tolerating the therapy or treatment sufficiently to allow administration of oral psilocybin and if treatments do not result in meeting any of the medical exclusion criteria outlined below * Moderate to severe symptoms of depression (GRID Hamilton Rating Scale for Depression \[GRID-HAMD\] \> 16) * English-speaking * Over the age of 18 * Have given written informed consent * Able to read * Be judged by study team clinicians to be at low risk for suicidality, as defined by a score of =\< 2 on the Columbia- Suicide Severity rating scale (C-SSRS) ideation subscale, 0 on the behavior subscale, and by overall clinical judgment; and * Have limited lifetime use of hallucinogens (the following criteria are preferred: no use in the past 5 years; total hallucinogen use less than 10 times) Exclusion Criteria: * GENERAL MEDICAL EXCLUSION CRITERIA * Participants who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing; participants who are of child-bearing potential and sexually active who are not practicing a highly effective means of birth control (i.e., implants, injectables, combined oral contraceptives, progestin containing intrauterine devices \[IUDs\], or vasectomized partner) * Participants with partners of child-bearing potential who are sexually active and not practicing a highly effective means of contraception (i.e., condom with spermicidal foam/gel/film/cream/suppository) * Cardiovascular conditions: Recent history of coronary artery disease or stroke, current uncontrolled angina, uncontrolled hypertension, a clinically significant electrocardiogram (ECG) abnormality as determined by a cardiologist and/or medical monitor (e.g., atrial fibrillation), prolonged corrected QT (QTc) interval (i.e., QTc \> 450 msec), artificial heart valve, or transient ischemic attack (TIA) in the past year * Systolic blood pressure (SBP) \> 139 mm HG; diastolic blood pressure (DBP) \> 89 mm HG; heart rate (HR) \> 90 bpm (mean values of the four or more assessments will not exceed 139 mm Hg systolic, 89 mm Hg diastolic, and/or 90 beats per minute) * Insulin-dependent diabetes * Non-insulin dependent diabetes if recent history of symptomatic hypoglycemia * Significant central nervous system (CNS) pathology. Some examples include: * Unstable primary or secondary (e.g., metastatic) cerebral neoplasm. Stable is defined as treatment within prior 4 weeks or no immediate plans for treatment. * Unstable history of seizures * Cerebral aneurysm - unstable with plans for intervention or close monitoring * Clinical diagnosis of dementia * Clinical diagnosis of delirium * In the investigator's opinion, abnormal and clinically significant results on the physical examination, vital signs, ECG, or laboratory tests at screening may constitute a risk for an individual exposed to psilocybin. This includes platelets below 100,000 platelets per cubic millimeter of blood, liver function tests three times the upper limit of normal, and creatine two times above the normal range. This also includes clinically significant abnormal electrolytes or low hemoglobin (below 10 g/L) * Any acute condition that would, in the Investigator's judgment, place the subject at significant risk due to safety concerns or compliance with clinical study procedures (e.g., electrolyte imbalance, infection/inflammation, intestinal obstruction, inability to swallow medication, etc.) * Under active treatment of an investigational agent in a clinical trial * In the judgement of the clinician, patients currently taking psychoactive medication on a regular (e.g., daily) basis (e.g., cannabis, opiates, Ritalin), other than a daily selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), or bupropion (\< 300 mg daily) (Patients will not be instructed to hold prescribed psychoactive medications) * In the judgement of the clinician, patients who self-report or urine test positive for psychoactive medications (e.g., illicit opiates, amphetamines, cocaine) may be excluded, for example recent use by self-report but urine test negative may still be enrolled, while participants with impaired mental status will be excluded * PSYCHIATRIC EXCLUSION CRITERIA * Current or past history of meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I or II disorder * Current or history within one year of meeting DSM-5 criteria for a moderate or severe alcohol or other drug use disorder (excluding caffeine and tobacco) * Have a first or second-degree relative with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition) or bipolar I or II disorder * Has a psychiatric condition that precludes the establishment of therapeutic rapport, as evidenced by long-term patterns of unstable relationships, a history of significant stress-related paranoia, and identity disturbances * History of a medically significant suicide attempt as determined by the study team and principal investigator (PI)