Psilocybin With 5-HT1A Blockade in Healthy Volunteers

Inclusion criteria:

* 21 - 60 years old
* Must give written or electronic informed consent
* Must have at least a high-school level of education or equivalent (e.g. GED) and are fluent in English
* Must be healthy and psychologically stable as determined by screening for medical and psychiatric problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests
* Must agree not to take any as needed (PRN) medications on the mornings of drug sessions
* Must agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each drug administration.
* Must agree to refrain from using all psychoactive substances within 24 hours or 5 elimination half-lives (whichever is greater) before psilocybin administration. Caffeine is the exception.
* Must have a negative urine toxicology report on the same day as drug dosing.
* Who are female and of child-bearing potential and are sexually active, must agree to use highly effective means of birth control (i.e. implants, injectables, combined oral contraceptives, progestin-containing intrauterine device (IUD) or vasectomized partner) for the duration of this study.
* Who are male and sexually active, must agree to use contraception and refrain from sperm donation within 90 days of completing dosing sessions. Effective methods of contraception are barrier, hormonal, and sterilization methods.

Exclusion Criteria:

* Are currently taking a medication with any significant pharmacokinetic or pharmacodynamic interactions with pindolol (e.g. beta-blockers or other anti-hypertensive medications).
* Have a history of orthostatic hypotension or low blood-pressure.
* Have elevated transaminases (2x the upper limit of normal)
* Have a Child-Pugh score that falls within classes B or C.
* Are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing.
* Have cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g. atrial fibrillation, corrected QT interval (QTc) \> 450 msec), artificial heart valve, symptomatic valvopathy, history of pulmonary hypertension or transient ischemic attack (TIA) in the past year; systolic blood pressure \> 139, diastolic blood pressure \> 89
* Have epilepsy or a history of seizures
* Have insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
* Are currently taking on a regular (e.g. daily) basis any medications having a centrally acting serotonergic effect, including monoamine oxidase inhibitors (MAOIs). For individuals who have intermittent or PRN use of such medications, psilocybin sessions will not be conducted until at least five half-lives of the agent have elapsed after the last dose.
* Have a current diagnosis of schizophrenia spectrum disorders
* Have a current diagnosis of bipolar spectrum disorders
* Have a current diagnosis of major depressive disorder or Generalized Anxiety Disorder
* Have a current diagnosis or history of substance induced psychotic disorder
* Have a current DSM-5 moderate or severe alcohol or drug use disorder (excluding caffeine and nicotine)
* Have a first degree relative with bipolar I disorder, or schizophrenia spectrum disorder.
* Have a psychiatric condition judged to be incompatible with establishment of safe exposure to psilocybin.
* Have a BMI ≥ 40
* Report a known history of sleep apnea, symptoms indicative of sleep apnea, or have an Apnea-Hypopnea Index (AHI) \> 15, or STOP BANG \>5
* Taking prescribed hypnotics or other medications known to alter sleep physiology: i.e., Z-drugs, Benzodiazepines, Orexin Agonists or Antagonist, Beta Blockers.
* Regularly taking over-the-counter sleep aids (inc. melatonin and diphenhydramine) and unwilling to abstain during the study.
* Insomnia Severity Index ≥ 10