The main purpose of the current studies is to evaluate the safety and tolerability of psilocybin in patients with chronic stroke.

Stroke is the leading cause of death and adult disability worldwide, and every year more than 795,000 people in the United States have a stroke. According to the National Stroke Association, only 10 percent of people who have a stroke recover completely, while 50 percent experience moderate to severe long-term disability, including significant impairment in language, cognition, motor, and sensory skills, which require special care or long-term care in a nursing home or other facility. Therefore, in the United States alone, nearly 400,000 people per year will suffer the lasting debilitating consequences of stroke. Previous studies have indicated that rehabilitation following stroke is constrained by a so-called 'critical' or 'sensitive' period. While this learning window can be extended or enhanced, once the post-stroke rehabilitation critical period has closed, clinically applicable manipulations that can reopen it are lacking.

Recently the investigators have shown that the psychedelic compounds like psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxmethamphetamine (MDMA) can reopen a novel critical period for social reward learning. The adage "you can't teach an old dog new tricks" captures a certain truth about the brain. Specifically, a young person's brain is much more malleable (e.g., able to make new motor-memories and store new motor-memories) compared to an adult's brain. Neuroscientists call these periods of heightened sensitivity to input "critical periods." Based on these observations the investigators posit that psychedelic compounds serve as the long sought-after "master key" for unlocking critical periods across the brain. Ongoing preclinical studies are examining this possibility, with the goal of determining the therapeutic potential of psychedelics (including psilocybin) as adjunct therapies for any intervention whose clinical efficacy may be constrained by critical period closure, including post-stroke rehabilitation.

The main purpose of the proposed studies is to evaluate the safety and tolerability of psilocybin in stroke patients (Phase 1). as a secondary aim the investigators will collect data on the efficacy of psilocybin in effecting motor recovery in post-stroke patients.

Inclusion Criteria:

• Over age 18 years, inclusive.
• Ischemic or hemorrhagic stroke confirmed by CT or MRI, at least 12 months prior to admission date
• Ability to give informed consent and understand the tasks involved.
• Agree that, for the study duration, will refrain from: (1) No new prescription medications during the time of the study without approval of the study team, (2) taking any herbal supplement (except with prior approval of the research team), (3) taking any nonprescription medications with the exception of: 1. non-steroidal anti-inflammatory drugs. 2. acetaminophen. 3. vitamins. 4. or other over-the-counter medications approved by the research team
• Are willing to follow restrictions and guidelines concerning medications, consumption of food, beverages, and nicotine the night before and just prior to psilocybin administration.
• Agree to have transportation other than driving themselves home or to where the participants are staying after the administration of psilocybin.
• Are willing to be contacted via telephone for all necessary telephone contacts.
• Must have a negative pregnancy test if able to bear children.
• Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal.
• Must agree to inform the investigators within 48 hours of any new medical conditions and procedures.
• Are proficient in speaking and reading English.
• Agree to have all clinical visit sessions recorded to audio and video.
• Agree to not participate in any other interventional clinical trials during the duration of this study.

Exclusion Criteria:

• Taking one of the following medications in the 30 days prior to psilocybin administration:

  1. selective serotonin reuptake inhibitor (SSRI)
  2. Serotonin-norepinephrine reuptake inhibitors (SNRI)
  3. Buproprion
  4. Valproic acid
  5. Zolpidem
  6. Trazodone
  7. Carbamazepine.
  8. tricyclic antidepressants
  9. Monoamine Oxidase Inhibitors
  10. Mirtazapine

  l. Lithium m. Buspirone n. Atypical antipsychotics o. Zolpidem p.Carbamazepine q. Clonazepam r. Gabapentin s. Lamotrigine t. Levetiracetam u. Phenobarbital v. Phenytoin w. Topiramate x. Valproic Acid y. Zonisamide

• History of medically significant suicide attempt.

• Evidence of acute cardiac dysfunction as evidenced by either elevated troponin or EKG changes within 48 hours of administration.

• Systolic blood pressure that is greater than 150 mmHg systolic on > 2 readings during the 7-day monitoring period AND blood pressure medication management has been assured.

• Diastolic blood pressure that is greater than 100 mmHg systolic on > 2 readings during the 7-day monitoring period AND blood pressure medication management has been assured.

• Systolic blood pressure is less than 90 mmHg systolic on > 2 readings during the 7-day monitoring period after blood pressure medication management has been assured.

• Diastolic blood pressure is less than 30 mmHg systolic on > 2 readings during the 7-day monitoring period after blood pressure medication management has been assured.

• Systolic blood pressure exceeds 160 mmHg or is less than 90 mmHg immediately prior to administration of psilocybin; patients are allowed to be on anti-hypertensives.

• Diastolic blood pressure exceeds 100 mmHg or is less than 30 mmHg immediately prior to administration of psilocybin; patients are allowed to be on anti-hypertensives.

• Cognitive impairment that, in the estimation of the study team, would preclude the use of the MindPod Dolphin.

• History of physical or neurological condition that interferes with study procedures or assessment of motor function (e.g. severe arthritis, severe neuropathy, Parkinson's disease).

• Social and/or personal circumstances that interfere with ability to perform follow up assessments.

• Are pregnant or nursing.

• Weigh less than 48 kg.

• Are not able to give adequate informed consent.

• Are actively abusing opioids, cocaine, Phencyclidine (PCP), amphetamines, or alcohol.

• Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID-5) criteria for moderate or severe substance use disorder

• Diagnosis of schizophrenia, history of prior psychosis, anxiety requiring hospitalization, or Type 1 bipolar.

• Hypernatremia

• Hypokalemia (but can have received repletion during the prior 24 hours)

• Hyperkalemia

• Glomerular filtration rate of < 30 ml/min

• Elevated of white blood cell count

• Hemoglobin < 7 g/dl

• Platelet count < 100,000 g/dl

• Acute cardiac dysfunction demonstrated by either troponin elevation (chronic elevation is acceptable), or EKG changes suggestive of acute coronary syndrome.

• Active suicidal ideation as assess by the C-SSRS.

Phase 1 safety trial requires no blinding.