Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin (NECTAR) in Aging and Alzheimer's Disease
Trial Snapshot
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Enrollment
- 200
- Locations
- 1
- Primary Endpoint
- Determine whether psilocybin enhances neuroplasticity (Neuroplasticity Composite Score (NPCS))
Study Overview
Brief Summary
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.
Detailed Description
Study Description:
A randomized, open-label, parallel-group clinical trial with two arms aimed at evaluating whether psilocybin enhances the neuroplastic and cognitive benefits of cognitive training in two populations: older adults with normal cognition and individuals with early-stage Alzheimer s disease (AD). Participants in both populations will be randomized to receive either two oral doses of 25 mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks or cognitive training alone for four weeks. The primary outcome will be the change from baseline in a novel Neuroplasticity Composite Score (NPCS) assessed four weeks after the first psilocybin session or the onset of cognitive training. Secondary outcomes include the assessment of safety and tolerability, cognitive performance on TabCAT, RBANS, and autobiographical memory; psychological well-being; quality of life; and sleep. Additional outcomes will include MRI/fMRI/MRS measures of neuroplasticity, brain network connectivity and neurochemistry; EEG during sleep; and plasma and plasma extracellular vesicle (EV)-associated biomarkers of synaptic integrity, serotonergic transmission, neurodegeneration, mitochondrial function, and inflammation. Screening will include clinical and cognitive assessments, assessment of suicidal ideation and behavior, biomarker confirmation of AD pathology, neuroimaging eligibility screening, and laboratory tests for metabolic, hepatic, and renal function. A urine drug screen will confirm the absence of illicit substances, and a urine pregnancy test will be required for female participants of childbearing potential. By simultaneously assessing cognitive and brain function and structure at multiple levels, this study will provide proof-ofconcept for psilocybin s potential to promote neuroplasticity, enhance cognition, improve emotional well-being, and mitigate neurodegenerative processes in aging and AD. Additionally, the inclusion of understudied geriatric populations will address critical gaps in psilocybin s safety and efficacy profile in older adults.
Objectives:
Primary Objective:
-Determine whether psilocybin enhances neuroplasticity four weeks after the first psilocybin session compared to cognitive training alone.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 65 Years to 120 Years (Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •INCLUSION CRITERIA:
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •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-
- •Cognitively normal population: No cognitive impairment based on history and examination, with a CDR score of 0 and MoCA score >=
- •For participants with early-stage AD, evidence of underlying AD pathology by the only FDA-approved blood-based test, Lumipulse G p217-Tau/Abeta42 ratio >= 0.
- •Alternatively, participants who 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 results 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 remain stable through the psilocybin dosing period and primary outcome assessments, unless a change is medically necessary.
- •Concurrent pharmacotherapy with a single selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic anti-depressant (TCA) or monoamine oxidase inhibitor (MAOI) is allowed if the participant is willing and able to taper off this medication after Visit 1 (Screening) and stay 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
- •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 not 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 Criteria
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Medical history
- •-Neurological disorders (besides AD): Brain disorders, either previously diagnosed or revealed through screening exams or baseline neuroimaging, including:
- •Stroke (except single asymptomatic old lacune)
- •Transient Ischemic Attack (TIA) within the past year, unless work-up shows no ongoing risk
- •Extensive microvascular pathology or microbleeds
- •Multiple sclerosis or demyelinating disorders
- •Parkinson s disease or 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
- •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
- •History of psychotic disorders unless remote, short-lived, and directly attributable to medication misuse or overdose
- •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
- •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. Participants taking a single SSRI, SNRI, TCA, or MAOI 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 requires participant agreement, prescribing-clinician agreement, and investigator determination of no elevated risk. A written taper/monitoring plan and point of contact must be documented. Weekly safety check-ins will assess discontinuation symptoms, mood/anxiety, sleep, and suicidality. If clinically significant worsening occurs, taper may be slowed, paused, stopped, or the participant excluded for safety.
- •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, high-grade conduction disease, or other rhythm/conduction abnormalities). 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 >=5 minutes seated rest using 3 readings averaged.
- •Resting heart rate (HR) <= 55 bpm or > 100 bpm or clinically significant arrythmia: HR will be assessed concurrently with the blood pressure protocol above.
- •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 m2)
- •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
- •Typical & atypical antipsychotics
- •Multiple antidepressants medications (i.e., combinations of SSRIs, SNRIs, MAOIs, TCAs and bupropion). Bupropion (<= 300 mg/day) is permitted without taper or washout if the dose has been stable for >= 6 weeks before screening.
- •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 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 taking lithium will be eligible only if (i) lithium is being used for a condition where supervised discontinuation is clinically appropriate (e.g., augmentation for unipolar depression or another non-bipolar indication), (ii) there is no history of bipolar disorder/mania, and (iii) the prescribing clinician confirms that a gradual taper and washout can be completed safely before baseline/dosing. During any lithium taper/washout, participants will be monitored for symptom recurrence and safety concerns; if relapse risk is unacceptable, participants will be excluded from further study participation.
- •Sildenafil, tadalafil, or similar medications should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
- •UGT1A10 and 1A9 inhibitors (e.g., diclofenac, probenecid) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
- •Alkaline phosphatase inhibitors (e.g., cinacalcet) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
- •Serotonin agonists (e.g., migraine medications like triptans) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
- •Serotonergic supplements, such as St. John s Wort, should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
- •For the purposes of these medication criteria, regular use means scheduled/daily use or PRN use on >= 3 days per week over the prior 4 weeks. Intermittent PRN use means <= 1 day per week on average over the prior 4 weeks (and no evidence of physiologic dependence, in the judgment of the medically responsible investigator).
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Arms & Interventions
early-stage Alzheimer's Disease (AD) population - cognitive training plus psilocybin
older adults with early-stage AD, two oral doses of 25mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks
Intervention: Cognitive Training (Other)
Normal Cognition population - cognitive training only
Older adults with normal cognition, 4 weeks of cognitive training alone
Intervention: Cognitive Training (Other)
early-stage Alzheimer's Disease (AD) population - cognitive training only
older adults with early-stage AD, 4 weeks of cognitive training alone
Intervention: Cognitive Training (Other)
Normal Cognition population - cognitive training plus psilocybin
Older adults with normal cognition, two oral doses of 25mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks
Intervention: Cognitive Training (Other)
early-stage Alzheimer's Disease (AD) population - cognitive training plus psilocybin
older adults with early-stage AD, two oral doses of 25mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks
Intervention: Psilocybin (Drug)
Normal Cognition population - cognitive training plus psilocybin
Older adults with normal cognition, two oral doses of 25mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks
Intervention: Psilocybin (Drug)
Outcomes
Primary Outcomes
Determine whether psilocybin enhances neuroplasticity (Neuroplasticity Composite Score (NPCS))
Time Frame: 4 weeks
two doses, 25 mg each, of psilocybin given two weeks apart plus 4 weeks of cognitive training vs. cognitive training alone.
Secondary Outcomes
- Assess the safety and tolerability of psilocybin in cognitively healthy older adults and individuals with early-stage AD.(6 weeks)