Assessment of Psilocybin (TRP-8802) in Concert With Psychotherapy in Patients With Irritable Bowel Syndrome (IBS)

Inclusion Criteria: Age

1. Participant must be 21 to 64 years of age, inclusive, at the time of signing theinformed consent form. Type of Participant and Disease Characteristics
2. Participant has a body mass index (BMI) between 18.5 and 29.9
3. Have a clinical diagnosis of IBS (any subtype) as defined by the Rome IV clinicalcriteria:
4. Abdominal pain at least 4 days per month over at least 2 months associated with one ormore of the following: i. Related to defecation ii. A change in frequency of stool iii. A change in form (appearance) of stool iv. After appropriate evaluation, the symptoms cannot be fullyexplained by another medical condition
5. Have "treatment resistant" IBS (Rajagopalan 1997) by having all of the following:
6. symptoms for more than 12 months by history
7. received adequate explanation and reassurance for symptoms as documented by agastroenterologist in the medical record. This means the patient's primarygastroenterologist will document that they have conducted an evaluation that iswithin appropriate standards of practice to exclude other medical conditions, andthat in their opinion irritable bowel syndrome is the most appropriate diagnosis.The patient's primary gastroenterologist will also document that they havediscussed this evaluation and diagnosis with the patient.
8. tried at least one dietary intervention by history
9. tried at least one pharmacologic agent for at least six weeks by history
10. Have attempted a gut-brain behavior therapy for at least six weeks by history
11. Concurrent psychotherapy is allowed if the type and frequency of the therapy has beenstable for at least 2 months prior to screening and is expected to remain stableduring participation in the study.
12. Participant must not use tobacco or other nicotine containing products (e.g., vapepens) by history.
13. Participant must be medically stable as determined by screening for medical problemsvia a personal interview and/or, a medical questionnaire, and an ECG, within 1 monthof starting active intervention (performed during screening).
14. Participant must agree to consume approximately the same amount of caffeine-containingbeverage (e.g., coffee, tea, cola) that he/she consumes on a usual morning, beforearriving at the research unit on the mornings of TRP 8802 session days. If theparticipant does not routinely consume caffeinated beverages, he/she must agree to notdo so on the TRP 8802 session day
15. Participant must agree to refrain from using any psychoactive drugs, includingalcoholic beverages and nicotine, within 24 hours before and after each TRP 8802administration. The exception is caffeine.
16. Participant must agree to not take triptan medications (e.g., sumatriptan) within 72hours before and after each TRP 8802 administration.
17. Participant must agree to not take sildenafil (Viagra®), tadalafil, or similarmedications within 72 hours before and after each TRP 8802 administration.
18. Participant must agree to not take any pro re nata (PRN) medications on the morningsof TRP 8802 sessions.
19. Participant must agree that for 7 days before each TRP 8802 session, he/she willrefrain from taking any nonprescription medication, cannabis, nutritional supplement,or herbal supplement except when approved by the Principal Investigator. Exceptionswill be evaluated by the Principal Investigator and will include acetaminophen,non-steroidal anti-inflammatory drugs, osmotic laxatives, stimulant laxatives,secretagogues such as linaclotide and lubiprostone, birth control, thyroid hormones,and common doses of vitamins and minerals.
20. Participant must have at least a high school level of education or equivalent (e.g.,General Educational Development [GED] Test).
21. Participant must demonstrate ability to track abdominal pain and stool frequency andconsistency daily in the ePRO system.
22. Participant must demonstrate ability to wear watch with heart rate tracking capabilityfor daily heart rate tracking.
23. Participant must be willing to attempt fMRI scan and EEG. Sex andContraceptive/Barrier Requirements
24. Contraceptive use by women and men should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies.Adequate birth control methods include intrauterine device,injected/implanted/intravaginal/transdermal hormonal method, oral hormones plus abarrier contraception, abstinence, vasectomized sole partner, or double barriercontraception. Subjects will be excluded if they cannot use highly effective birthcontrol for any reason. If a potential subject lives in an area where localregulations preclude the use of adequate contraception (intrauterine device,injected/implanted/intravaginal/transdermal hormonal method, oral hormones plus abarrier contraception, abstinence, vasectomized sole partner, or double barriercontraception), study enrollment will not be allowed.
25. If a participant is opting for abstinence as their birth control method, onlytrue/total abstinence is permitted. Periodic abstinence (e.g., calendar,ovulation, symptothermal, post-ovulation methods), lactational amenorrhea, andwithdrawal are not acceptable. Counseling regarding the importance of maintainingabstinence, and the potential risks of exposure to a developing embryo or fetuswill be provided during the preparatory sessions during the Preparation 1session, Integration 1 session, and during Deep Phenotyping 2.
26. Females of reproductive potential must agree to use effective birth control forthe duration of active intervention (defined as the time from the Baseline [deepphenotyping] visit until 6 months and 3 days (for female subjects) after DeepPhenotyping/EOT visit. Female subjects must agree to not donate eggs, orparticipate in in vitro fertilization for the duration of the recommendedcontraceptive use of the trial.
27. Sexually active male participants and/or their female partners must agree to useeffective birth control for the duration of active intervention (defined as thetime from the Baseline [deep phenotyping] visit until the 3 months and 3 days (for male subjects) after Deep Phenotyping/EOT visit of the male participant.Male participants must also agree not to donate sperm for the duration of activeintervention. Informed Consent
28. Participant has provided informed consent as described in Appendix 1 which includescompliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria: Medical Conditions

1. Participant has the following vital sign measurements (taken after 5 minutes ofsitting down) during screening visit: SBP>139 mmHg, DBP > 89 mmHg, and/or HR > 90bpm
2. Participant has a history of valvular heart disease reported during screening
3. Participant has a history of pulmonary hypertension reported during screening
4. Participant has moderate to severe hepatic impairment (Child Pugh Class B and C) asdetermined by presence of ascites or encephalopathy and scoring of albumin, bilirubin,and INR on screening labs
5. Participant has one of the following gastrointestinal medical conditions: inflammatorybowel disease (ulcerative colitis or Crohn's disease), celiac disease, chronicidiopathic constipation, or eosinophilic esophagitis reported during screening
6. Participant has had (within the past 1 year) a cardiovascular condition such ascoronary artery disease, stroke, angina, uncontrolled hypertension, a clinicallysignificant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e.,QTc > 450 msec), artificial heart valve, or transient ischemic attack reported duringscreening
7. Participant has epilepsy with a history of seizures reported during screening
8. Participant has insulin-dependent diabetes reported during screening
9. Participant is taking an oral hypoglycemic agent and has a history of hypoglycemia.
10. Participant has active auto-immune disease (e.g., lupus, rheumatoid arthritis)reported during screening
11. Participants has any clinically significant lab abnormalities per a complete bloodcount and metabolic panel (e.g., elevated liver enzymes) at time of screening, andadditional screening labs to exclude organic disease within the past two years. Pleasesee screening in Section 4.2. Cutoffs requiring exclusion from the study are listedbelow: Lab Panel Test Cutoff for Exclusion CBC White Blood Cell Count >17 K/uL CBC Hemoglobin <11.5 g/dL CBC Platelets <150 K/uL Metabolic Panel Sodium <130 or >150 Metabolic PanelPotassium <3.2 or > 5.5 Metabolic Panel CO2 <23 or >32 BUN >40 (2X ULN) Creatinine >1.3 Liver Enzymes Direct bilirubin >1.0 Liver Enzymes AST > 80 (2x ULN) Liver EnzymesALT > 55 (ULN) Clotting Factors INR >4
12. Participant has a current or past history of meeting Diagnostic and Statistical Manualof Mental Disorders, 5th edition (DSM-5) criteria for schizophrenia spectrum or otherpsychotic disorders (except substance/medication-induced or due to another medicalcondition), or bipolar I or II disorder measured via SCID-5 and SCID-5-PD.
13. Participant has a current or past history (within 1 year) of meeting DSM-5 criteriafor a moderate or severe alcohol, tobacco, or other drug use disorder (excludingcaffeine) measured via relevant questions from the SCID-5 during screening
14. Participant meets Rome IV criteria for the diagnosis of centrally mediated abdominalpain syndrome (CAPS). Other co-morbid Rome IV diagnoses will not be exclusioncriteria.
15. Participant has a history of a medically significant suicide attempt, meaning asuicide attempt leading to an emergency room visit or inpatient hospitalization forany length of time.
16. Participant does not meet institutional guidelines and safety measures for MRI (e.g.,has metal in the body or severe claustrophobia) Prior/Concomitant Therapy
17. Participant is taking psychoactive prescription medication (e.g., opioids, tramadol,benzodiazepines) on a regular basis (i.e., more than 2 times a week).
18. Participant is currently taking an antidepressant or neuromodulator, including SSRIs,SNRIs, and TCAs. Participants will also be required to refrain from usingantidepressant medications through the completion of primary outcome assessments.Note: if a participant self-initiates a medication taper with the consent and supportof their physician, they can re-screen after the appropriate time period.
19. Participant has taken any antidepressant medication for at least 2 weeks (or at least 4 weeks for fluoxetine) prior to the Screening visit.
20. Participant is currently taking on a regular (e.g., daily) basis any medicationshaving a primary centrally-acting serotonergic effect, including monoamine oxidaseinhibitors (MAOIs). For individuals who have intermittent or PRN use of suchmedications, TRP 8802 sessions will not be conducted until at least 5 half-lives ofthe agent have elapsed after the last dose.
21. Subjects taking serotonin-acting dietary supplements (such as 5-hydroxy-tryptophan orSt. John's wort) due to the potential for their interaction with psilocybin andincreased safety risks.
22. Subjects taking prohibited medications. The list of prohibited medications includesantihypertensive medications (any ACE-I, ARB, beta blocker, or calcium channelblocker), UGT1A9 or 1A10 inhibitors (e.g., regorafenib, rifampicin, phenytoin,eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole,deferasiroxor, ginseng) and aldehyde or alcohol dehydrogenase inhibitor (e.g.,disulfiram).
23. Participant does not agree to refrain from cannabis use and the use of all otherpsychoactive medications and drugs of abuse during the study
24. Participant is currently taking prohibited drugs of abuse, including methamphetamine,illicit opioids (e.g., heroin), cocaine, 3,4-methylenedioxymethamphetamine (Ecstasy/Molly), or hallucinogens (e.g., mescaline or peyote).
25. Participant has any use of hallucinogens in the past 6 months or has had a totallifetime hallucinogen use of 10 or more times.
26. Participant tests above 0.02% blood alcohol content on breath alcohol testing and/orpositive for cocaine, methamphetamine, or opioids on urine drug testing.
27. Participant has a psychiatric condition judged to be incompatible with establishmentof rapport or safe exposure to TRP 8802. Prior/Concurrent Clinical Study Experience
28. Participant is currently in another clinical trial. Diagnostic assessments
29. Participant has a significant suicide risk as defined by:
30. suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past yearat Screening or at Baseline; or
31. suicidal behaviors within the past year; or
32. clinical assessment of significant suicidal risk during participant interviewsOther Exclusions
33. Participant is pregnant (as indicated by a positive urine pregnancy test assessed atScreening and before the TRP 8802 session) or nursing.
34. Participant is a WOCBP and sexually active, or a man and sexually active, and notpracticing an effective means of birth control.
35. Participant has a confirmed first- or second-degree relative with schizophreniaspectrum or other psychotic disorders (except substance/medication-induced or due toanother medical condition), or bipolar I or II disorder.
36. Participant is unable to complete 10/14 days of ePRO tracking during run-in period.