Investigating the Persisting Effects of a Single Dose of Psilocybin on Structural Plasticity in Healthy Older Adults

The investigators will use cognitive exams, perceptual tasks, brain imaging, peripheral psychophysiology, and surveys to investigate the persisting effects of psilocybin on cognition, predictive coding, and affect in healthy older adults. The investigators will measure changes in these measures by comparing baseline to one-week and one-month post-treatment. Participants will be randomly assigned to receive a dose of psilocybin in a range from microdose to moderate-to-high dose. Dose response will be assessed. Anatomical magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) will be used to assess changes in brain structure, while functional magnetic resonance imaging (fMRI) will be used to quantify changes in functional brain activity. The investigators will assess whether changes in these brain measures underlie observed changes in cognition, predictive coding and affect.

The investigators will use cognitive exams, perceptual tasks, brain imaging, peripheral psychophysiology, and surveys to investigate the persisting effects of psilocybin on cognition, predictive coding, and affect in healthy older adults. The investigators will measure changes in these measures by comparing baseline to one-week and one-month post-treatment. Participants will be randomly assigned to receive a dose of psilocybin in a range from microdose to moderate-to-high dose. Dose response will be assessed. Anatomical magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) will be used to assess changes in brain structure, while functional magnetic resonance imaging (fMRI) will be used to quantify changes in functional brain activity. The investigators will assess whether changes in these brain measures underlie observed changes in cognition, predictive coding and affect.

The data from this study will provide a strong foundation for future studies to further investigate the effects of psychedelic-induced plasticity on cognition, predictive coding and affect. These experimental studies will be conducted in participants with no diagnosable mental health conditions, but the resulting mechanistic insights may inform development of treatments that use psychedelics to help individuals shift from pathological patterns of thought, emotion, and behavior to more healthy and adaptive ones. This information will be crucial for designing and optimizing mental health treatments using psychedelic agents. Furthermore, these studies may also reveal biomarkers that can then be used to predict the likelihood of a patient's response to a particular type of therapeutic intervention.

This project will include healthy older adults (60-85 years old), allowing us to characterize the dose-dependent effects of psilocybin, from the acute subjective experience to long-term persisting effects, in old age. Studying the effects of psilocybin in old age may inform the development of treatments that use psychedelics to improve cognition and affect in older adults by promoting brain changes that oppose the effects of synaptic dysfunction in aging and neurodegeneration in Alzheimer's disease.

Eligibility Criteria:
Inclusion Criteria:

Are 60-85 years of age at time of Informed Consent Form signing. Are able and willing to adhere to study requirements, including attending all study visits, preparatory and follow-up sessions, and completing all study evaluations.

Are able to swallow capsules. Women of childbearing potential (WOCBP) must agree to practice an effective means of birth control throughout the duration of the study.

Have normal or corrected-to-normal vision as determined by the study staff. Written informed consent obtained from and ability for subject to comply with the requirements of the study.

Have an identified support person and agree to be accompanied home (or to an otherwise safe destination) by the support person, or another responsible party, following dosing.

Agree to inform the investigators within 48 hours of any new or changed medical conditions during the course of their study participation.

Have access to a quiet space and a computer to perform online assessments.

Exclusion Criteria:

Breastfeeding, have a positive pregnancy test at screening or at any point during the course of the study, or unwilling to practice birth control during participation in the study.

Have a current psychiatric disorder, general medical condition, or other problem or abnormality that, in the opinion of the study clinician or PI, could compromise safety, render them unsuitable for the study, or would make them unable to comply with study activities.

Have MRI contraindications (e.g., metal implants, pacemakers, claustrophobia etc.) as determined by an MRI contraindications questionnaire.

In the baseline C-SSRS, the study clinician records the presence of active suicidal ideation (SI) with an intent and/or plan or any history within the past year of SI with an intent and/or plan as indicated by a positive response ("Yes") to Questions 4 or 5 on the C-SSRS SI questions; or presence of active suicidal behavior or any history within the past 5 years of suicidal behavior including suicide attempt (including actual attempt, interrupted attempt, or aborted attempt), preparatory acts for suicide attempt, or non-suicidal self-injurious behavior as indicated by a positive response ("Yes") to any suicide behavior questions of the C-SSRS.

Have a history of a psychotic disorder, bipolar disorder (type I or II), or a dissociative disorder (determined by history).

Family history (first degree relative) of primary psychotic disorder, primary bipolar disorder, or hallucinogen-induced psychotic disorder, if participant \< 30 years old.

History of Hallucinogen Persisting Perception Disorder (HPPD). History of a seizure disorder in adulthood, central nervous system (CNS) metastases or current symptomatic CNS infection.

History of intracerebral hemorrhage, embolic stroke, transient ischemic attack (TIA), or history of any aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.

History of valvulopathy or pulmonary hypertension. Uncontrolled hypertension (Systolic BP\>139mmHG or Diastolic BP\>89mmHG) or tachycardia (average HR\>90bpm) averaged over at least two measurements.

Clinically significant cardiovascular disease (e.g., history of myocardial infarction or congestive heart failure); or baseline QT/QTc\>500msec; or baseline QT/QTc 451-500msec with repeat QT/QTc \>500msec.

Poorly controlled diabetes mellitus (e.g., history of an episode of severe hypoglycemia or hospitalization for hyperglycemia on the current diabetes regimen).

Inadequate hepatic function as determined by total bilirubin or alkaline phosphatase \>3x institutional upper limit of normal; or AST or ALT \>6x institutional upper limit of normal. However, participants with Gilbert syndrome are allowed to enroll.

Inadequate renal function as determined by eGFR \< 30 mL/min/1.73 m2 (based on the MDRD equation) or CrCl \< 30 mL/min (based on the C-G equation).

The regular use of psychotropic medications, such as antidepressants (i.e., SSRIs, tricyclic antidepressants, and monoamine oxidase inhibitors), antipsychotics, and mood stabilizers.

Concomitant dosing of psilocybin with known UGT1A10 and UGT1A9 inhibitors (e.g., diclofenac and probenecid) will be avoided. \[There is no exclusion criterion based on the use of medications or substances that are inhibitors or inducers of CYP450 enzymes.\]

The use of Prohibited Medications:

Serotonin Reuptake Inhibitors (SSRIs and SNRIs) Tricyclic Antidepressants (TCAs) Monoamine Oxidase Inhibitors (MAOIs) Atypical antidepressants (e.g., mirtazapine, trazodone, buspar) Antipsychotics/Neuroleptics (typical and atypical) Anti-epileptics or mood stabilizers (e.g., lithium, valproate) (does not include gabapentin used for non-epilepsy conditions) Efavirenz (Sustiva, in Atripla) Lorcaserin Over-the-counter supplements intended to affect mood or anxiety (e.g., 5HT-P, SAMe or St. John's Wort).

Other drugs associated with the serotonin syndrome (e.g., ondansetron) used within 48 hours of study drug administration.

Vasoactive drugs (e.g., sildenafil, sumatriptan, calcium channel blockers) used within 48 hours of study drug administration.

Unable to agree to the following required Lifestyle Modifications: Patients will be asked to refrain from consuming alcohol, cannabinoids, prescription analgesics/stimulants/benzodiazepines, and any recreational drugs for 48 hours before, the day of, and for 48 hours after study drug administration. Participants will be advised to consume their usual amount of coffee, tea, or other caffeine-containing beverages on the morning of their Medication Visits.

Have a recent history of suicidal ideation or attempted suicide that, in the opinion of the study clinician or PI, may present a risk of suicidal or self-injurious behavior.

Have received an investigational drug or taken a psychedelic, entactogen, or dissociative anesthetic within 30 days of the screening visit Have taken a psychedelic drug (e.g., psilocybin, lysergic acid diethylamide (LSD-25), mescaline) \>15 times in last 30 years Have taken a psychedelic drug (e.g., psilocybin, LSD-25, mescaline) \>0 times in last 3 months Have taken an entactogen (e.g., 3,4-methylenedioxymethamphetamine (MDMA), 3,4-Methylenedioxyamphetamine (MDA)) \>15 times in last 30 years Have taken an entactogen (e.g., MDMA, MDA) \>0 times in last 3 months Have taken a dissociative anesthetic (e.g., ketamine, Phencyclidine (PCP)) \>15 times in last 30 years Have taken a dissociative anesthetic (e.g., ketamine, PCP) \>0 times in last 3 months Have an allergy or intolerance to any of the materials contained in the investigational drug product.

Has been diagnosed with any disease that impairs motor function (e.g., Parkinson's disease) At high risk of falls as determined by study physician considering medical history, screening of recent symptoms and medications, and functional mobility testing.