Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin

Starting soon · Phase 2

Conditions studied: Alzheimer's Disease

In brief

Background: Normal aging, as well as dementias such as Alzheimer s disease, can cause changes in the brain that affect memory, attention, and thinking. Researchers want to know if regular mental tasks (cognitive training) can improve brain function in older adults. They also want to know if psilocybin, a compound found in certain mushrooms, can further support improved brain function. Objective: To learn how regular cognitive training, with or without psilocybin, can improve brain health in older adults. Eligibility: People aged 65 years and older with mild cognitive impairment or early-stage Alzheimer s disease. Healthy older adults with normal cognition are also needed. Design: Participants will be screened. They will have a test of their heart function and an imaging scan. They will have mental health screening and tests of their thinking and memory. They will practice brain-training tasks on a tablet. Participants will be divided into 2 groups: 1 will have cognitive training plus psilocybin; 1 will have cognitive training only. Those having cognitive training only will have 5 or 6 clinic visits. They will take the tablet home to practice brain training daily. They will wear a device to measure brain waves as they sleep; they may have 1 overnight stay in the clinic, or they may wear the device at home. Imaging scans and other tests will be repeated at each visit. Those taking psilocybin will have up to 9 clinic visits. In addition to the visits for cognitive training, they will take 1 psilocybin capsule by mouth 2 weeks apart (the second dose is optional). They will remain in the clinic for 24 hours after each dose.

Key facts

Study ID: NCT07721467
Run by: National Institute on Aging (NIA)
People needed: 200
Starts: 2026-10-01
Expected to finish: 2030-12-31
Last updated by the study team: 2026-08-07

Who can join

Age: 65 and older, up to 120. Sex: any. Healthy volunteers: accepted.

You may not qualify if…

An individual who meets any of the following criteria will be excluded from participation in this study:
Medical history
-Neurological disorders (besides AD): Clinically significant brain disorders, either previously diagnosed or revealed through the screening exams or baseline neuroimaging, including:
Stroke (except single asymptomatic old lacune)
Transient Ischemic Attack (TIA) within the past year, unless full work-up reveals no ongoing risk
Extensive microvascular pathology or microbleeds
Multiple sclerosis or related demyelinating disorders
Parkinson s disease or related movement disorders (e.g., Multiple Systems Atrophy, Progressive Supranuclear Palsy)
Brain tumors
History of meningitis or encephalitis
History of moderate/severe traumatic brain injury (Glasgow Coma Scale <= 12)
Other dementias (e.g., vascular dementia, mixed neurodegenerative-vascular dementia, Lewy body disease, frontotemporal dementia, primary progressive aphasia, Huntington s disease, corticobasal degeneration)
Epilepsy
Stable, mild neurological conditions (e.g., migraine, essential tremor, peripheral neuropathy) may be allowed at the discretion of the medically responsible investigator.
-Psychiatric disorders:
Current or past moderate-to-severe mood disorders (e.g., treatment-resistant depression, bipolar disorder)
History of psychotic disorders (e.g., schizophrenia, schizoaffective disorder, bipolar disorder) unless psychosis was remote, short-lived, and directly attributable to medication misuse or overdose
Suicidal ideation or behavior: Active suicidal ideation (C-SSRS severity 2-5) within the past 1 month or any suicidal behavior within the past 6 months; or current elevated acute risk in the opinion of the medically responsible investigator based on C-SSRS plus clinical interview.
Severe PTSD, defined as a Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) score >= 4 in men or >= 3 in women
Anxiety or personality disorders, if moderate to severe, as determined by the medically responsible investigator.
Mild depression and/or anxiety may be permitted if successfully treated with psychotherapy and/or single anti-depressant agent (i.e., SSRI, SNRI, TCA, MAOI or bupropion). However, given the potential for serotonergic antidepressants to blunt psilocybin s effect or increase risk124,125, participants taking a single SSRI, SNRI, TCA, or MAOI other than fluoxetine may still be eligible only if they are willing and able to taper off this medication after Visit 1 (Screening) and complete a washout period of at least 7 +/- 2 days prior to Visit 2 (Baseline) and at least 14 +/- 2 days prior to Visit 3 (for the Psilocybin + Cognitive Training group) or Visit 4 (for the Cognitive Training alone group). Tapering of eligible non-fluoxetine antidepressants will be treated as an eligibility criterion and will occur only when all of the following are true: (i) the participant wishes to proceed after discussion of risks/benefits, (ii) the prescribing clinician agrees tapering is reasonable and safe, and (iii) the medically responsible investigator agrees there is no elevated risk based on psychiatric history, current symptoms, and overall clinical picture. Discontinuation will not be abrupt. A written taper plan (dose-reduction schedule and monitoring plan) will be documented in coordination with the prescribing clinician, including a clear point of contact if symptoms worsen. During taper/washout, the study team will conduct scheduled weekly safety check-ins by phone focused on withdrawal/discontinuation symptoms, mood/anxiety worsening, sleep disruption, and suicidal ideation/behavior. If clinically significant symptom worsening or other safety concerns occur, the taper will be slowed, paused, or stopped, and clinical management will be redirected to the treating clinician; the participant may be excluded from further participation for safety reasons.
Cardiovascular conditions:
Any history of coronary artery disease
Clinically significant electrocardiographic (EKG) abnormalities (e.g., atrial fibrillation/flutter, QTc > 450 ms, evidence of myocardial infarct history, highgrade conduction disease, or other rhythm/conduction abnormalities) as determined by the PI/medically responsible investigator. For EKG abnormalities other than QTc > 450 ms, clinical significance may be corroborated by transthoracic echocardiogram (TTE).
Uncontrolled hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg) confirmed after appropriate rest and repeated measurements: blood pressure will be measured in the seated position after >= 5 minutes of quiet rest, using an automated device and appropriate cuff size; three measurements will be obtained 1-2 minutes apart, and the average of them will be used for eligibility determination (a repeat set may be obtained after additional rest if initial readings are elevated).

Where it is running

National Institute of Aging, Clinical Research Unit — Baltimore, Maryland, United States

Full record on ClinicalTrials.gov

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