The Efficacy of Psilocybin Therapy for Depression in Parkinson's Disease

Inclusion Criteria: * Able to understand and provide informed consent * Comfortable speaking and writing in English * Have neurologist-diagnosed idiopathic Parkinson's disease (PD), Hoehn and Yahr stages 1 to 3 during an "on" phase (time when medication/DBS for parkinsonian motor feature, including bradykinesia and rigidity is in effect) * Have no changes in medication or major surgical procedures anticipated for treatment duration * Have a score \>/=20 on the Beck Depression Inventory-2 (BDI-2), consistent with moderate or greater depressive symptom severity, at Baseline. * For people who can become pregnant: agree to use highly effective contraception from entry into the trial through Day B30 assessments (4 weeks after the second psilocybin administration session) and agree to not breastfeed. Acceptable methods of contraception are: An intrauterine device (IUD), hormone-based contraceptives (birth control pills) , condoms (internal or external) must be used with another method (other than spermicide), and complete abstinence from sexual activity that could result in pregnancy. * Agree that for one week preceding each psilocybin session, they will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the research team. Exceptions will be evaluated by the research team and assessed for safety. Agree to abstain from all tobacco and nicotine use for the duration of the study. * Agree to consume approximately the same amount of caffeine-containing beverages that they usually consume before arriving at the research unit on the mornings of psilocybin administration sessions. * Agree to avoid sedative-hypnotic medications (e.g., benzodiazepines, zolpidem, zopiclone, zaleplon) taken on an as-needed basis for a minimum of 5 half-lives prior to each psilocybin administration session and for 24 hours after each psilocybin administration session. * Agree to avoid opioid medications taken on an as-needed basis for a minimum of 5 half-lives prior to each psilocybin administration session and for 24 hours after each psilocybin administration session. * Agree not to use products or substances containing Δ9-tetrahydrocannabinol (THC) and/or cannabidiol for at least 7 days prior to each psilocybin administration session and for 24 hours after each psilocybin administration session. * Agree to not use non-prescribed narcotics (eg. heroine, fentanyl), depressants (eg. Barbiturates, benzodiazepines) and/or inhalants for the duration of participation in the trial. * Agree not to consume alcoholic beverages for at least 24 hours prior to and 24 hours following each psilocybin administration session. * Have a primary care provider, neurologist, or psychiatrist who is actively managing or coordinating care and is available for consultation with the study medical monitor. Exclusion Criteria: * Any indication of forms of parkinsonism other than idiopathic Parkinson's disease. * Cognitive impairment, defined as a Montreal Cognitive Assessment (MoCA) score \<24. * Symptomatic orthostatic hypotension. * Currently receiving electroconvulsive therapy (ECT) or treatment via transcranial magnetic stimulation (TMS). Previous treatment with ECT and/or TMS is permitted; last treatment must be at least 30 days prior to entry into this trial. * Treatment in a clinical trial within 30 days of entry into this trial or treatment with another investigational drug or other intervention within 30 days or 5 half-lives, whichever is longer, prior to entry into this trial. * Pregnancy as indicated by a positive urine pregnancy test during screening, lactation, or the intention of becoming pregnant within 3 months of entry into this trial. * Current severity of psychiatric symptoms warranting immediate treatment as determined by the study medical staff (e.g. due to inability to provide for basic needs/safety). The study medical staff will assess these individuals, determine the appropriate level of care, and coordinate with the individual's primary providers to ensure close follow-up. * High risk of self-harm/suicide, as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS) risk screen, specifically: participant answers "yes" to item 4 or 5 suggesting intent to act on suicidal thoughts OR participant has made a serious suicide attempt within the 12 months prior to entry into this trial. * History of meeting DSM-5 criteria for a schizophrenia spectrum disorder, other psychotic disorder, or a mood disorder with psychotic features. * History of delusional symptoms or any other psychotic symptoms accompanied by a loss of insight. Exceptions may be made at the investigators' discretion in cases of a history of psychotic symptoms that were attributable to substance or medication use. * Current delusional symptoms or any other psychotic symptoms accompanied by a loss of insight. * History of a schizophrenia spectrum disorder in a first-degree relative. * History of bipolar disorder 1 in a first-degree relative, in whom illness onset was prior to age 40. * Current or history of meeting DSM-5 criteria for a bipolar disorder. * Current or history within the last 2 years of meeting DSM-5 criteria for a moderate or severe alcohol or drug use disorder, excluding caffeine. * Currently meeting DSM-5 criteria for another psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin treatment procedures as determined by the investigators. * History of meeting DSM-5 criteria for Hallucinogen Persisting Perception Disorder (HPPD). * History of using any psychedelic substances including psilocybin, lysergic acid diethylamide (LSD), mescaline (and natural products containing mescaline including peyote and San Pedro cactus), N,N-Dimethyltryptamine (DMT), natural products containing DMT including ayahuasca and 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine, 2C compounds, 3,4-methylenedioxy-methamphetamine (MDMA), or methylone during the past 6 months at dosages and/or frequencies determined clinically significant by the investigators. * Cancer with known central nervous system (CNS) involvement, CNS infection, or other major CNS disease aside from PD. * Epilepsy or other seizure disorder in adulthood. * Supplemental oxygen requirement. * Allergy or intolerance to any of the materials contained in the drug products. * Renal insufficiency defined as creatinine clearance \< 40 ml/min using Cockraft and Gault equation * Insufficiently managed endocrine conditions, including diabetes mellitus and clinically significant thyroid dysfunction. * Cardiovascular conditions, including: * Elevated blood pressure defined as systolic blood pressure (SBP) \>150 or diastolic blood pressure (DBP) \>95 taken during Enrollment * Tachycardia defined as heart rate (HR) \>90 beats per minute taken during Enrollment * Bradycardia defined as HR \<50 bpm taken during Enrollment * Angina * History of stroke within the past year * Clinically significant ECG abnormality as determined by the investigators, including but not limited to QTc \> 450 * Hepatic dysfunction as indicated by any of the following laboratory values: * AST \> 3 x upper limit of normal * ALT \> 3 x upper limit of normal * Total bilirubin \> 3.0 mg/dl * Use of any of the following concomitant medications AND inability/unwillingness to discontinue for at least 5 times the elimination half-life of the agent (specific exceptions are noted) prior to psilocybin administration, including: * Agents that may be associated with serotonin syndrome: * MAO inhibitors (participants must have discontinued 2 weeks prior to baseline) * St. John's Wort * S-adenosyl-methionine (SAM-e) * 5-Hydroxytryptophan (5-HTP) * Dextromethorphan * Opioids (e.g., codeine, fentanyl, hydrocodone, meperidine, tramadol) * Lithium * Linezolid * Buspirone * Agents that may interact with psilocybin metabolism/effects: * Serotonin antagonists (e.g., cyclobenzaprine, ondansetron) * Antipsychotics * Other dopamine antagonists (e.g., metoclopramide, promethazine, prochlorperazine) * Nicotine * Modulators of uridine diphosphate (UDP) or glucuronosyltransferase (UGT) (e.g. valproate, diclofenac, mefenamic acid, verapamil, ketoconazole, itraconazole, probenecid, phenobarbital, protease inhibitors) * L-methyl folate (\>/= 7.5mg/day) * Efavirenz * Agents that may increase the risk of psychotic symptoms: * Stimulants (e.g. modafinil, methylphenidate, atomoxetine, methamphetamine, cocaine, amphetamine derivatives) * Anticholinergics (e.g. benztropine, trihexyphenidyl, scopolamine, hyoscyamine) * Systemic steroids * Tricyclic antidepressants * Other medical condition or diagnosis, concomitant medication(s), physical exam finding, laboratory abnormality or health risk identified that precludes participation in study procedures due to safety or feasibility concerns at the discretion of the investigators.