This study will serve as a pilot randomized controlled trial to assess the feasibility of Psilocybin-Assisted Psychotherapy (PAP) in Treating Irritable Bowel Syndrome (IBS). Patients with severe IBS will undergo 3 pre-psychotherapy sessions with two licensed and trained psychedelic therapists, then will be randomized to undergo a guided psychotherapy session with single 25 mg oral "high" dose of psilocybin or a single 100 mg dose of niacin (active placebo) and attend 4 post-therapy integration sessions.

Inclusion Criteria:

• Severe IBS patients meeting Rome IV criteria. Severe IBS is defined by IBS-SS >300, or one or more emergency room (ER) visit for abdominal pain in the last year.
• Experiencing persistent IBS symptoms despite pharmacologic therapy
• Have an identified support person
• Agree to be accompanied home (or to an otherwise safe destination) by the support person, or another responsible party, following dosing
• Participants of childbearing potential must agree to practice an effective means of birth control throughout the duration of the study.
• Participants must agree to send outside medical records in order for the study team to verify eligibility.

Exclusion Criteria:

• Unstable medical conditions or serious abnormalities on complete blood count, chemistries, or ECG that in the opinion of the study physician would preclude safe participation in the trial. Some examples include:

  • Congestive heart failure
  • Clinically significant arrhythmias (e.g.,
  • Ventricular fibrillation, torsades) or clinically significant ECG abnormality (i.e., corrected QT interval > 450)
  • Recent acute myocardial infarction or
  • Evidence of ischemia (in the last year)
  • Malignant hypertension
  • Congenital long QT syndrome
  • History of valvular heart disease
  • Acute renal failure
  • Moderate to Severe hepatic impairment (Child Pugh class B and C).
  • Respiratory failure
  • Recent stroke (< 1 year from signing of consent)
  • Laboratory tests abnormalities (ALT ≥ 2X upper limit of normal (ULN), aspartate aminotransferase (AST) ≥ 2X ULN, Hemoglobin<11.5, platelets <150, White Blood Cells (WBC)>10, Sodium>150, Potassium K<3.5 or K>5.2)
  • Abnormal and clinically significant results on the physical examination (BP>139/89 mmHG), heart rate (HR)>90bpm,
  • History of Pulmonary hypertension

• Significant central nervous system (CNS) pathology. Examples include:

  • Primary or secondary cerebral neoplasm
  • Epilepsy
  • History of stroke
  • Cerebral aneurysm
  • Dementia
  • Delirium

• Primary psychotic or affective psychotic disorders. Examples include current or past DSM-5 criteria for:

  • Schizophrenia spectrum disorders
  • Schizoaffective disorder
  • Bipolar I or II disorder with psychotic features
  • Major Depressive Disorder
  • Substance induced psychotic disorders
  • Paranoid personality disorder
  • Delusional disorder
  • Borderline personality disorder
  • Any other psychotic illness

• Family history of psychotic or serious bipolar spectrum illnesses. Examples include first-degree relative with:

  • Schizophrenia spectrum disorders
  • Schizoaffective disorder
  • Bipolar I disorder with psychotic features
  • Any other psychotic illness

• High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation. Examples include:

  • Agitation
  • Violent behavior

• Active substance use disorders (SUDs) defined as Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for moderate or severe alcohol or drug use disorder (excluding caffeine and nicotine) within the past year

• Clinically significant suicidality or high risk of completed suicide defined as:

  • 'Yes' to C-SSRS Suicidal Ideation items 4 or 5 within the last 2 months at Screening or 'since last visit' at Baseline
  • Any C-SSRS Suicidal Behavior item within the past 12 months at Screening or 'since last visit' at Baseline, as defined by 'Yes' to any of the following on the C-SSRS: actual attempt, interrupted attempt, aborted attempt, or preparatory acts
  • Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, that presents a serious risk of suicidal or self-injurious behavior

• History of hallucinogen persisting perception disorder (HPPD)

• Pregnancy/lactation

• Cognitive impairment as defined by: Montreal Cognitive Assessment Test (MoCA) < 23

• Concurrent Medications

  • Antidepressants
  • Centrally-acting serotonergic agents (e.g., monoamine oxidase inhibitors (MAOIs))
  • Antipsychotics (e.g., first and second generation)
  • Mood stabilizers (e.g., lithium, valproic acid)
  • Aldehyde dehydrogenase inhibitors (e.g., disulfiram)
  • Significant inhibitors of UGT 1A0 or UGT 1A10
  • Niacin

• Subjects should not also be taking serotonin-acting dietary supplements (such as 5-hydroxy-tryptophan or St. John's wort)

• Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, Benzodiazepines, Cocaine, Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), Methadone, Opiates (Morphine, Oxycodone), Phencyclidine (PCP)

• Have a psychiatric condition judged to be incompatible with establishment of rapport with the study therapists or safe exposure to psilocybin

• Have any psychological or physical symptom, medication or other relevant finding prior to randomization, based on the clinical judgment of the PI or relevant clinical study staff that would make a participant unsuitable for the study.

• Have an allergy or intolerance to either psilocybin on Niacin

• Be enrolled in another clinical trial assessing intervention(s) for anxiety, depression, and/or existential distress (e.g., pharmacologic or psychotherapeutic interventions)

• Are unable to provide external medical records or refuse to provide external medical records.

Individual participant data (IPD) will not be made available to other researchers.