This study is being conducted to understand changes in brain activity following administration of two different drugs (Psilocybin and Dextromethorphan) in older adults with low well-being.

The main questions it aims to answer are, does psilocybin:

1. Acutely increase complexity of EEG activity in older adults with low well-being, as modulated by the presence of biomarkers of Alzheimer's disease (AD) pathology.
2. Longitudinally decrease plasma markers of neuroinflammation, as modulated by the presence of biomarkers of AD pathology.
3. Explore longitudinal changes in autonomic physiology via wearable recording devices as well as longitudinal structural and functional brain changes measured in the MRI

Participants will be in the study for up to 3 months, which will include 3 to 4 in person visits and 3 to 4 remote visits. Most visits will be between 1 to 3 hours, but the dosing visit will last a minimum of 8 hours and could be as long as 12 hours. During the dosing visit, all participants will receive a single dose of the study drugs and dosages listed below.

Researchers will compare participants who receive the following drug options:

• A low-to-moderate dose of Psilocybin (5-10 mg)
• A moderate-to-high dose of Psilocybin (25-30 mg)
• A low-to-moderate dose of Dextromethorphan (30-60 mg)
• A moderate-to-high dose of Dextromethorphan (80-90 mg)

The eligibility criteria are deliberately incomplete to preserve the scientific integrity of the study.

Inclusion Criteria:

• Are between 50-85 years inclusive at time of consent signing
• Have below-average well-being, defined by the World Health Organization Well-Being Index (WHO-5)
• Have no cognitive impairments, indicated by a Mini-Mental State Examination (MMSE) score >24
• Have an identified willing contact person with at least weekly contact with the participant to be able to provide meaningful information about the participant's daily function and able to pick up the study participant at the end of the Dosing Visit
• Participants assigned female sex at birth must be non-lactating, and post-menopausal, defined as a period of over 12 months since the last menstrual period, or otherwise physically unable to become pregnant
• Participants assigned male sex at birth must 1) refrain from sperm donation for 3 months after the Dosing Visit, and 2) if engaging in sexual activities that may result in pregnancy, must use a condom, plus their partner of childbearing potential must use a second, highly effective form of contraception for 3 months after the Dosing Visit
• Be proficient in English
• Are able and willing to provide consent as assessed by comprehension questions in informed consent process
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Ability to swallow oral medications (capsules)

Exclusion Criteria:

General:

• Have a known allergic or severe reaction to Psilocybin, Dextromethorphan, or any of the non-active components of the IMP capsules
• Insufficient ability to report on symptoms to make a valid assessment on any required instrument
• Have a condition or presence of clinical feature which, in the opinion of the investigators might interfere with or prevent appropriate study participation or interfere with data interpretation

MRI Exclusions:

• Any implanted object or device that poses a safety risk or could interfere with MRI scanning (e.g. aneurysm clips, cardiac pacemakers, defibrillators, neurostimulators, cochlear implants, spinal cord stimulators, insulin or infusion pumps, metallic prostheses or fragments, heart valves, vascular stents, or shunts. surgical staples, clips, or joint replacements, radiation seeds, medication patches containing metal, or any other metallic or electronic implants)
• History of metallic injury to the eyes or body, or those with tattoos containing metallic ink, permanent makeup, or body piercings that cannot be removed.
• Any condition that poses a safety risk or could interfere with MRI scanning (e.g. severe claustrophobia or motion disorders or breathing problems, etc)

Psychiatric:

•History of hallucinogen persisting perception disorder (HPPD) (as per DSM-5 criteria)

Cardiovascular:

• Clinically significant cardiovascular conditions e.g., clinically significant EKG abnormalities, transient ischemic attack in the last 6 months, history of hemorrhagic stroke, history of myocardial infarction within 1 year of signing informed consent form (ICF)
• Baseline (heart rate < 60 bpm or > 90 bpm at screening or pre-dose
• Baseline hypertension (≥140 SBP or ≥90 DBP), after repeated measurements
• QTc Interval > 450msec on 12-lead EKG. Note: If QT-prolonging medications are started or increased in dose after enrollment and prior to dosing visit, a repeat EKG must be done >12-hours after this change to assure continued safe enrollment in the trial
• Clinically significant arrhythmia (e.g., uncontrolled atrial fibrillation, or untreated supraventricular tachycardia)
• Any current condition where physical activity is associated with palpitations, anginal pain or syncope

General health:

• Major systemic disorders, including seizure, insulin dependent diabetes mellitus, recent history (last 12 months) of advanced cancer or its treatment (radiation therapy or chemotherapy), had major surgery within 6 months from screening or plans to have surgery while enrolled in the study
• Inadequate hepatic function as determined by total bilirubin or alkaline phosphatase >3x institutional upper limit of normal; or aspartate aminotransferase (AST) or alanine transaminase (ALT) >3x institutional upper limit of normal. However, participants with Gilbert syndrome are allowed to enroll
• Inadequate renal function as determined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (based on the MDRD equation)
• Participant is at increased risk of falls