Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin
This study is looking at whether psilocybin, a compound found in certain mushrooms, can help improve brain function when combined with regular mental exercises (cognitive training). Researchers want to see if this combination can help older adults, including those with early-stage Alzheimer's disease or mild memory problems. You would receive either two doses of 25 mg psilocybin two weeks apart, along with four weeks of cognitive training, or just the cognitive training for four weeks. The main goal is to see if psilocybin helps improve brain plasticity (the brain's ability to change and adapt), measured at four weeks. The study aims to enroll 200 participants aged 65 to 120 years old. The current recruitment status is unclear.
- Study design
- This is a randomized, open-label study with two groups. It will involve 200 participants.
- What's involved
- You would undergo screening, a heart function test, and an imaging scan. You would also receive two oral doses of 25 mg psilocybin (if in that group) and participate in daily cognitive training for four weeks.
- Compensation
- Not stated in the trial record.
- Follow-up
- The main outcome is measured at four weeks after the first psilocybin session or the start of cognitive training.
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NCT07721467
Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin
Not Yet Recruiting
PHASE2Ages 65+InterventionalNational Institute on Aging (NIA)Government-funded
~200 participants
Updated 2026-07-24 on ClinicalTrials.gov
What's tested:PsilocybinCognitive Training
At a glance
Recruiting sites
0 of 1 listed site is recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Determine whether psilocybin enhances neuroplasticity (Neuroplasticity Composite Score (NPCS))
Measured over 4 weeks
Conditions
Where it's being run
1 sites across 1 statesMaryland1
Study leadership
- Dimitrios I Kapogiannis, M.D. · PRINCIPAL_INVESTIGATOR · National Institute on Aging (NIA)
Who to contact
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Do you actually qualify for this trial?
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Eligibility criteria
Inclusion
Capacity to provide informed consent.
Stated willingness to comply with all study procedures and availability for the duration of the study.
Male or female, age \>= 65 years old.
Cognitive Status:
Early-stage AD population: Meets the 2024 Alzheimer s Association Workgroup revised criteria for diagnosis and staging of AD (symptomatic cognitive impairment consistent with amnestic MCI or mild AD dementia) with a CDR score of 0.5-1(including 0.5 for the memory box) and a Montreal Cognitive Assessment (MoCA) score of 20-25.5
Cognitively normal population: No cognitive impairment based on clinical history and examination, with a CDR score of 0 and MoCA score \>= 26.
For participants with early-stage AD, evidence of underlying AD pathology by the currently only FDA-approved blood-based test, Lumipulse G p217-Tau/Abeta42 ratio \>= 0.00738.123 Alternatively, participants who had previously underwent amyloid PET or CSF testing for diagnosis of AD (to qualify for treatment with anti-amyloid monoclonal antibodies or for any other reason) may provide report of the amyloid PET scan or result of CSF analysis compatible with underlying AD pathophysiology; Lumipulse G p217- Tau/Abeta42 will still be measured to maintain consistency in study assessments, but values \< 0.00738 will not disqualify them.
Absence of serious neuropsychiatric symptoms, defined as a score of 0 on Delusions and Hallucinations items and a score \<= 2 on Anxiety, Aggression, Irritability, and Disinhibition items of the Neuropsychiatric Inventory Questionnaire (NPI-Q).
Acetylcholinesterase inhibitors and/or memantine are permitted (alone or in combination) provided the dose(s) have been stable for (Bullet) 6 weeks prior to screening and are expected to remain stable through the psilocybin dosing period and primary outcome assessments, unless a change is medically necessary as determined by the prescribing clinician.
Concurrent pharmacotherapy with a single selective serotonin reuptake inhibitor (SSRI) other than fluoxetine, serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic anti-depressant (TCA) or monoamine oxidase inhibitor (MAOI) is allowed only if the participant is willing and able to taper off this medication after Visit 1 (Screening) and have stayed off it for 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). Bupropion (\<= 300 mg/day) is permitted without taper or washout if the dose has been stable for \>= 6 weeks before screening.
Absence of active suicidal ideation with plan/intent and no suicidal behavior within the past 6 months, as defined by Columbia-Suicide Severity Rating Scale (C-SSRS) of 0 or 1. Participants with passive ideation (severity 1) may be included only if risk is judged low, a safety plan is documented, and there is no suicidal behavior in the prior 6 months.
For the early-stage AD population, participation of a study partner who is willing and able to serve as a medical history informant, accompany participants during visits, and provide psychological support following psilocybin sessions. For the cognitively normal population, participation of a study partner will be encouraged, but will not be mandated as eligibility criterion.
Ability to take oral medication.
Pregnancy prevention:
Participants of childbearing potential must have a negative urine pregnancy test at screening and prior to psilocybin on Visits 3 and 7, and agree to use highly effective birth control beginning at least 14 days before any psilocybin dosing day and continuing through 30 days after the last psilocybin dose.
Male participants with partners of childbearing potential must agree to use condoms and to ensure their partner uses a highly effective contraceptive method during the same window. Sperm donation is not permitted during the study and for 30 days after the last psilocybin dose.
Exclusion
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
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.
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).
Resting heart rate (HR) \<= 55 bpm or \> 100 bpm or clinically significant arrythmia: HR will be assessed concurrently with the blood pressure protocol above (seated after \>= 5 minutes of rest), using the same repeated-measurement approach and corroborated by clinical assessment/EKG when indicated.
Clinically significant cardiomyopathy (e.g., hypertrophic, dilated, restrictive) or heart failure
Moderate to severe valvular heart disease (valvulopathy) or pulmonary hypertension
Metabolic disorders:
Insulin-dependent diabetes mellitus
Renal impairment (eGFR \< 60 ml/min/1.73 m\^2)
Liver function tests \> 2x upper limit of normal
Infectious \& Hematologic Conditions:
Positive HIV, HBV, or HCV status
Anemia (HGB \< 12 g/dL in men, \< 11 g/dl in women)
Poor venous access
Medications Exclusions
Absolute
Typical \& atypical antipsychotics
Multiple antidepressants medications (i.e., combinations of SSRIs, SNRIs, MAOIs, TCAs and bupropion). Participants taking a single SSRI, SNRI, MAOI, or TCA may still be eligible, if they are willing and able to taper off this medication after Visit 1 (Screening) and have stayed off it for 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). Participants currently taking fluoxetine will be excluded at screening because of the long half-life of fluoxetine and its active metabolite norfluoxetine.126 The study team will not direct fluoxetine tapering for the purpose of study participation. Participants taking fluoxetine will be advised to discuss with their own physician(s) whether they still need to be on fluoxetine and whether they could safely taper it and stay off it for some period of time. If they are willing to do that and their physician(s) decide to stop fluoxetine, they may come back and be re-screened for this study at a later time, after at least 4 weeks have passed since the last fluoxetine dose (they would also need to otherwise meet eligibility criteria). Bupropion (\<= 300 mg/day) is permitted without taper or washout if the dose has been stable for \>= 6 weeks before screening.
Relative
Benzodiazepines and non-benzodiazepine sedative-hypnotics (e.g., zolpidem, eszopiclone):
Regular use: participants must be willing and able to taper off and remain off for at least 14 +/- 2 days prior to Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group), due to potential confounding effects on EEG recordings and sleep architecture and potential attenuation of the acute psilocybin experience. Because benzodiazepine withdrawal can cause clinically significant symptoms (and, rarely, seizures), tapering must be gradual. Discontinuation schedule will be directed by the medically responsible investigator in coordination with the prescribing clinician per participant wishes; participants with evidence of physiologic dependence or for whom safe tapering is not feasible within the study timeline will not be eligible for further study participation.
Intermittent PRN use: participants may be eligible if they can hold these medications for at least 72 hours prior to each psilocybin dosing session (for the psilocybin + cognitive training group) and avoid use during the overnight EEG recording window.
Sleep-inducing medications (e.g., trazodone, sedative-hypnotics) should not be taken for at least 14 +/- 2 days before Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group) (due to potential confounding effects on EEG recordings and sleep architecture)
Melatonin (and similar over-the-counter sleep aids) should not be taken for at least 72 hours prior to Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group), due to potential confounding effects on EEG recordings
Mood stabilizers (e.g., lithium), long-acting opioids (unless they are willing and able to taper off after Visit 1 (Screening) and have stayed off ...
What this trial measures
- Determine whether psilocybin enhances neuroplasticity (Neuroplasticity Composite Score (NPCS))4 weeks
two doses, 25 mg each, of psilocybin given two weeks apart plus 4 weeks of cognitive training vs. cognitive training alone.