Twenty healthy adults (≥21 years old) will be enrolled to evaluate the efficacy of a single oral dose of psilocybin (25 mg) administered with or without pretreatment using oral pimavanserin (34 mg) or placebo. Outcome assessments will occur at 1 week and 1 month following psilocybin administration.

The purpose of this study is to clarify the receptor-level mechanisms underlying psilocybin's effects on mood and well-being, along with the associated neurophysiologic signatures. These mechanisms will be examined using psychometric scales, autonomic and fMRI-based neurophysiologic markers, and integrated pharmacokinetic/pharmacodynamic modeling.

Inclusion Criteria:

• Adults aged 21 to 65 years old
• Fluency in English
• At least high school level of education
• Right-handed
• Female participants of childbearing potential must agree to use a highly effective method of contraception throughout the study. Highly effective methods are defined as those that, when used consistently and correctly (alone or in combination), are associated with a failure rate of less than 1% per year. Condoms alone are not considered highly effective. Abstinence is not considered a highly effective method. However, at the investigator's discretion, abstinence may be accepted if, based on the investigator's judgment and knowledge of the participant's usual and preferred lifestyle, it can be reasonably expected to result in 100% effectiveness.
• Agree to abstain from any psychoactive drugs on the day prior to and the day of the drug administration session as demonstrated by a negative toxicology report.
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days.
• Agree not to take any PRN medications on the mornings of drug sessions
• Agree that for one week before the drug session, he/she will refrain from taking any nonprescription medication, nutritional or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.

Exclusion Criteria:

• Non-English speakers and those with language or hearing impairments
• Left-handedness (assessed by the Edinburgh Handedness Inventory)
• Any lifetime history of psychedelic use, including serotonergic compounds (e.g., psilocybin, LSD, mescaline, DMT, 5-MeO-DMT) and nontraditional psychedelics (e.g., MDMA, ketamine, ibogaine)
• Presence of cardiac, pulmonary, vascular, renal, hepatic, or other significant medical comorbidities
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, and HR >90 bpm), a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc > 450 msec), heart valve, or TIA in the past year
• QTc interval prolongation exclusionary criteria: medications known to prolong the QT interval (including: Class 1A antiarrhythmics (e.g., quinidine, procainamide), Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotics (e.g., ziprasidone, chlorpromazine, thioridazine), certain antibiotics (e.g., gatifloxacin, moxifloxacin), subjects with congenital prolongation of the QT interval; subjects with family history positive for long QT syndrome; subjects with a history of cardiac arrhythmias; and subjects with history of any cardiovascular disorder/condition known to increase the possibility of QT prolongation and torsades de pointes (i.e., symptomatic bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, heart failure, or Brugada Syndrome).
• Lifetime history of serious psychiatric or neurological disorders, including bipolar disorder, psychosis, or seizure disorder
• Lifetime history of severe substance use disorder
• Current (within past six months) substance use disorder of moderate or greater severity
• Clinically significant suicidal ideation (with strong intent or means) within the past 6 months or lifetime history of suicide attempt, current suicidal ideation, or otherwise judged by a study clinician to be more than low risk for suicidality
• Current use/positive toxicology for illicit drugs at screening and prior to drug administration session (includes illicit, non-prescribed, or prohibited substances such as amphetamines, barbiturates, buprenorphine, benzodiazepines, cocaine, MDMA, methadone, opioids, phencyclidine (PCP), and tetrahydrocannabinol (THC))
• Nicotine user consuming the equivalent of ≥ 10 cigarettes/day
• Altered gastrointestinal anatomy [history of surgeries that promote a general intestinal malabsorption (e.g., jejunoileal bypass, jejunocolic bypass, roux-en-Y gastric bypass, vertical banded gastroplasty, gastric band, gastric stapling, sleeve gastrectomy, biliopancreatic diversion with partial gastrectomy, distal gastric bypass, duodenal switch)]
• Weight < 40kg
• Have a first degree relative with schizophrenia or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I disorder
• MRI contraindications (e.g., claustrophobia incompatible with MRI scanning, medical device or implant incompatible with MRI, prior history as a metal worker and/or certain metallic objects in the body). Must complete MRI screening form and be approved by MRI technologist before each scan.
• Unable or unwilling to perform study procedures, or inappropriate for further study participation as determined by the PI and/or study clinicians