A Double Blind, Randomized Trial Investigating the Safety, Feasibility, and Mechanisms of Psychedelics in Healthy Older Adults With Low Well-being as Moderated by Biomarkers for Preclinical Alzheimer's Disease
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)
• 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)