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

The purpose of this study is to understand whether people with Parkinson's Disease and depression have improvement in their symptoms after psilocybin therapy.

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 \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 \ 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.