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).
-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 ...
