The purpose of this study is to assess the effects of 5-HT1A receptor blockade on the acute subjective effects of psilocybin, as measured through subjective survey measures and acute electroencephalography (EEG). Further, the investigators will assess the effects of psilocybin on post-acute sleep and dreaming through the use of sleep EEG and sleep and dream diaries.

This double-blind, randomized, cross-over study (N = 18) will administer a moderate dose of psilocybin trihydrate (18 mg, equivalent to 15 mg psilocybin anhydrate), with pindolol (30 mg), or placebo to assess the effects of 5-HT1A receptor blockade on the acute subjective effects and the acute neurophysiological effects of psilocybin through the use of self-report measures and acute EEG. Participants will also complete sleep and dream diaries 10 days prior to and 10 days following each drug administration session as well as wear an at-home sleep EEG device for 5 days prior to and 5 days following each drug session. This study aims to understand the mechanistic basis of the perceptual changes in the altered state of consciousness induced by psilocybin as well as its effects on post-acute sleep and dreaming.

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

De-identified data with no participant information will be shared on an open science platform to allow for independent analysis by other researchers. Subjective survey data, acute EEG, and sleep EEG data will be shared.