Treatment of gut-brain interaction disorders

Abstract

There is provided a method of treating or alleviating at least one symptom of a gut–brain interaction (DGBI) disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from psilocin, psilocybin, a derivative thereof, a crystalline form thereof, a cocrystal thereof, and a pharmaceutically acceptable salt thereof. The methods may involve inducing a psychedelic state in the subject and providing psychological support to the subject.

Description

TREATMENT OF GUT-BRAIN INTERACTION DISORDERSTechnical Field

[0001] The technology relates to the use of psychedelic compounds such as psilocin and psilocybin for the treatment disorders of gut-brain interaction such as irritable bowel syndrome.Cross-reference to related application

[0002] This application claims priority to US provisional patent application number 63 / 617,104 filed 3 January 2024, which incorporated by reference in its entirety.Background

[0003] Disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS), are prevalent, frequently disabling, and impose a major economic burden in the form of healthcare system utilization and work and school absenteeism.

[0004] IBS accounts for 30% - 50% of all gastroenterology consultations and effects approximately 10%- 15% of people worldwide. IBS is defined by the Rome IV criteria as at least weekly abdominal pain that is associated with eating or defecation. DGBI are estimated to impose an economic burden in the US of $28 billion annually. The annual direct and indirect medical costs of IBS in the US are estimated at $8B and $25B respectively. The IBS market is worth an estimated $14B and is underpenetrated relative to other Gl disorders for which there are more effective therapies available.

[0005] Despite the prevalence and social / economic costs of IBS, its pathogenesis is unclear and treatment regimens are varied. Visceral hypersensitivity, or aberrant afferent gut pain signaling and CNS dysregulation of pain modulation, is increasingly recognized as likely the largest driver of abdominal pain in IBS, with altered gut motility, immune activation, microbiome perturbation, and psychosocial disturbances also contributing. Diagnosis of IBS is symptom-based, with no reliable biomarkers, imaging, or functional testing findings. Pharmacologic treatments targeting pain-associated symptoms, such as prokinetic, laxatives for IBS with constipation, and antispasmodics for IBS with diarrhea are often employed. The pain associated with IBS often responds to neuromodulators such as tricyclic antidepressants (TCAs), and serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs).

[0006] Although there have been recent gains in understanding IBS, treatment remains challenging, with more than 50% of patients refractory to standard medical therapies.Approximately 75% of patients and 90% of gastroenterologists report dissatisfaction with the current treatment options.

[0007] Psilocybin and its active metabolite psilocin, are compounds with a large and growing evidence base for its safety and efficacy in a variety of psychiatric disorders. Psilocybin is a naturally occurring compound found in over 180 species of mushrooms that has predominantly serotonergic effects. In contrast to traditional psychopharmacologic regimens which require daily medication, the treatment paradigm for most psilocybin studies involves only one or two administrations of the medicine under controlled, supervised therapeutic settings, with an emphasis on preparatory sessions prior to and supportive 'integration' sessions following the psilocybin session(s).

[0008] The present inventors have developed a treatment for IBS using psychedelic compounds such as psilocybin and psilocin. In some embodiments the treatment also involves psychological support.Summary

[0009] In a first aspect, there is provided a method of treating a disorder of gut-brain interaction (DGBI) in a subject, the method comprising administering to the subject a therapeutically effective dose of a psychedelic compound selected from psilocin (4-hydroxy- N,N-dimethyltryptamine), psilocybin ([3-(2-dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate), 4-hydroxytryptamine, 4-hydroxy-N-methyltryptamine, [3-(aminoethyl)-1 H-indol- 4-yl] dihydrogen phosphate, [3-(2-trimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N,N,N-trimethyltryptamine, a derivative thereof, a crystalline form thereof, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, treating comprises alleviating at least one symptom of the DGBI. For example, the symptom may be selected from pain, abdominal discomfort, adnominal pain, cramping, bloating, excess abdominal gas, indigestion, changes in patterns of bowel movement, diarrhoea alternating with constipation, mucus in the stool, fatigue, depression, anxiety, abnormal bowel movement, stool form (appearance), frequency of bowel movements, urgency of bowel movements, or the feeling of incomplete bowel movement.

[0011] In another embodiment the method of treatment may comprise reducing one or more of the IBS-Symptom Severity Score (IBS-SSS), Visceral Sensitivity Index (VSI), Patient Global Impression of Change (PGI-C) score, Hospital Anxiety and Depression Scores (HADS); reducing pain; increasing the self-illness separation score (SIS Score); increasing glutamate / glutamine (Glx) in the anterior insula of the patient.

[0012] In one embodiment the IBS-Symptom Severity Score (IBS-SSS) is reduced by 50 points or more.

[0013] Preferably, the psychedelic compound is psilocin or psilocybin, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

[0014] The method may further comprise inducing a psychedelic state in the subject by administering the compound. For example, the psychedelic state may have a duration of 0.5, 1, 2, 3, 4, 5, or 6 hours.

[0015] Administration of the psychedelic may be subcutaneous, oral, intravenous, transdermal, intramuscular, intranasal, intranasal / pharanygeal, or buccal. Preferably administration is oral or intravenous.

[0016] The method may further comprise providing psychological support to the subject during the psychedelic state. For example the psychological support may be one or more of cognitive behavioural therapy, and mindfulness based therapy.

[0017] The method may further comprise providing psychological support after the patient has exited the psychedelic state, this may be in addition to or as an alternative to psychological support provided during the psychedelic state.

[0018] The DGBI may be irritable bowel syndrome (IBS), functional dyspepsia, or reflux sensitivity. For example the IBS may be diarrhea-predominant IBS (IBS-D), constipation- predominant IBS (IBS-C), or mixed-type IBS (IBS-M).

[0019] The IBS may be associated with an eating disorder, migraine, fibromyalgia, anxiety or depression.

[0020] In one embodiment the psychedelic is administered simultaneously or sequentially with at least one additional therapeutic agent.

[0021] The additional therapeutic agent may be selected from a non-steroidal antiinflammatory, prokinetic, laxative, antispasmodic, analgesic, tricyclic antidepressant, selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, a nonabsorbable antibiotic, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, opioid receptor modulator, guanylate cyclase 2C agonist, and a chloride channel-2 agonist.

[0022] The method may further comprise establishing severity or symptoms in a baseline period before the administration of the psychedelic.

[0023] In one embodiment the method improves one or more symptoms of IBS compared to the one or more symptoms in the baseline period.

[0024] The symptom is selected from pain, abdominal discomfort, adnominal pain, cramping, bloating, excess abdominal gas, indigestion, changes in patterns of bowel movement, diarrhoea alternating with constipation, mucus in the stool, fatigue, depression, anxiety, abnormal bowel movement, stool form (appearance), frequency of bowel movements, urgency of bowel movements, or the feeling of incomplete bowel movement. Preferably, the symptom is abdominal discomfort or adnominal pain.

[0025] The method may further comprise administering at least one further dose of the psychedelic, for example second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth dose.Definitions

[0026] Throughout this specification, unless the context clearly requires otherwise, the word ‘comprise’, or variations such as ‘comprises’ or ‘comprising’, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0027] Throughout this specification, the term ‘consisting of’ means consisting only of.

[0028] The term “consisting essentially of’ means the inclusion of the stated element(s), integer(s) or step(s), but other element(s), integer(s) or step(s) that do not materially alter or contribute to the working of the invention may also be included.

[0029] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present technology. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present technology as it existed before the priority date of each claim of this specification.

[0030] Unless the context requires otherwise, or specifically stated to the contrary, integers, steps, or elements of the technology recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

[0031] In the context of the present specification, the terms ‘a’ and ‘an’ are used to refer to one or more than one (i.e. , at least one) of the grammatical object of the article. By way of example, reference to ‘an element’ means one element, or more than one element.

[0032] In the context of the present specification, the term ‘about’ means that reference to a figure or value is not to be taken as an absolute figure or value but includes margins of variation above or below the figure or value in line with what a skilled person wouldunderstand according to the art, including within typical margins of error or instrument limitation. In other words, use of the term ‘about’ is understood to refer to a range or approximation that a person or skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.

[0033] The terms ‘treating’, ‘treatment’ and ‘therapy’ are used herein to refer to curative therapy, prophylactic therapy, palliative therapy and preventative therapy. Thus, in the context of the present disclosure the term “treating” encompasses curing, ameliorating, or tempering the severity of a psychological condition or one or more of its associated symptoms.

[0034] The terms ‘therapeutically effective amount’ or ‘pharmacologically effective amount’ or ‘effective amount’ refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated. The terms are synonymous and are intended to qualify the amount of each agent that will achieve the goal of improvement in disease severity and / or the frequency of incidence over treatment of each agent by itself while preferably avoiding or minimizing adverse side effects, including side effects typically associated with other therapies.

[0035] A ‘pharmaceutical carrier, diluent or excipient’ includes, but is not limited to, any physiological buffered (i.e. , about pH 7.0 to 7.4) medium comprising a suitable water soluble organic carrier, conventional solvents, dispersion media, fillers, carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Suitable water soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethylsulfoxide. Other conventional additives include lactose, mannitol, corn starch, potato starch, binders such as microcrystalline cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.

[0036] ‘Subject’ includes any human.

[0037] In the context of this specification, the term ‘administering” and variations of that term including ‘administer’ and ‘administration’, includes contacting, applying, delivering, or providing a compound or composition of the invention to a subject by any appropriate means.

[0038] Those skilled in the art will appreciate that the technology described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the technology includes all such variations and modifications. For the avoidance of doubt, the technology also includes all of the steps, features, and compoundsreferred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps, features and compounds.

[0039] In order that the present technology may be more clearly understood, preferred embodiments will be described with reference to the following description.Description of Embodiments

[0040] The methods disclosed herein involve the administration of a psychedelic compound such as psilocin or psilocybin to a subject to treat or prevent a gut-brain interaction (DGBI) disorder such as irritable bowel syndrome (IBS).Gut-brain interaction (DGBI) disorders

[0041] The methods disclosed herein are useful for the treatment or prevention of any DGBI disorder.

[0042] DGBI disorders are gastrointestinal conditions without underlying structural abnormality, for example no ulcers, cancer, or inflammation. Two of the most common DGBI include functional dyspepsia and irritable bowel syndrome (IBS). Functional dyspepsia is characterized by chronic, post-prandial discomfort or upper abdominal pain. IBS is characterized by chronic abdominal pain associated with a change in frequency or form of stool.

[0043] DGBI disorders can be diagnosed by any means known in the art. For example the modified Rome IV Questionnaire for Functional Gl Disorders includes 12 items that map on to DGBI criteria for functional dyspepsia (post-prandial distress syndrome and epigastric pain syndrome), IBS (constipation-predominant, diarrhea-predominant, mixed, unspecified), functional constipation, functional diarrhea, functional abdominal bloating / distension, and belching disorders. By using Rome IV, DGBI disorders can be diagnosed from a self-report questionnaire. DGBI disorder presence can be confirmed with the exclusion of structural abnormalities.

[0044] Examples of DGBI disorders that may be treated or prevented by the methods disclosed herein include irritable bowel syndrome (IBS), functional dyspepsia, or reflux sensitivity.

[0045] In preferred embodiments, the methods described herein are used to treat IBS, for example IBS is diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or mixed-type IBS (IBS-M).

[0046] The most common symptoms of IBS abdominal pain in association with altered stool form and / or frequency. The condition can further be characterized by a relapsing andremitting course. Subjects are typically sub-grouped according to the predominant stool pattern they report: diarrhea >25% of the time (IBS-D), constipation >25% of the time (IBS- C), or a mixed stool pattern of diarrhea and constipation >25% of the time (IBS-M).

[0047] Subjects with IBS may also exhibit a number of signs including sudden urges to have a bowel movement, abdominal pain or discomfort, gas, loose stools, frequent stools, nausea, mucus in stool, a feeling of being unable to empty their bowels.

[0048] In some embodiments the IBS is associated with at least one of the following: an eating disorder, migraine, fibromyalgia, anxiety, or depression.Methods

[0049] The methods involve oral or intravenous administration of a psychedelic compound. Other routes of administration may also be used, such as , intranasal, intranasal / pharyngeal, and buccal routes, transdermal. Parenteral administration via the subcutaneous and intra-muscular route are also contemplated. In some embodiments the methods also require the provision of psychological support to the subject by a therapist, psychiatrist, psychotherapist or other suitably qualified health professional.

[0050] In some embodiments, the methods comprise a single dose of about 0.01 mg / kg, about 0.02 mg / kg to about 0.5 mg / kg of the psilocin or psilocybin. Suitable single doses include about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, or about 0.5 mg / kg.

[0051] In some embodiments psychedelic compound is formulated into preparations for oral delivery. In some embodiments the oral formulation is a 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, or 50 mg tablet or capsule.

[0052] In some embodiments the psychedelic compound is isolated and purified. In some embodiments, it is synthesized.

[0053] In some embodiments the psychedelic compound is formulated in micelles. One example of micelles that find use in the disclosure is found in Orienti et al (Journal of Experimental and Clinical Cancer Research, 2019) which describes phosphatidylcholine micelles and is incorporated by reference herein. In some embodiments psilocybin is formulated in cyclodextrin and may find use in IV, oral or other forms of delivery. See Orienti et al. Cell Death and Disease (2019) 10:529, which is incorporated by reference herein.

[0054] The dose to be administered may be in the form of single doses of higher concentration, or divided doses of lower concentration. The concentration of any given dosewill depend on the frequency of administration. In some embodiments, depending on the formulation, the dose of psilocybin or psilocin will be around 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, or 0.5 mg / kg.

[0055] The dose may be an oral dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg of the psychedelic compound. Preferably, the dose is a 20 mg, 25 mg, 30 mg oral dose of the psychedelic compound.

[0056] In some embodiments the methods require that the subject does not enter a ‘psychedelic state’ or ‘dissociative state’.

[0057] In some embodiments the methods require the subject to enter a ‘psychedelic state’, or 'hallucinogenic state' which is characterized by effects that are placed into three categories: a. Perceptual effects: altered shapes and colors (often appearing brighter, more vivid, and intense); visual distortions; visual hallucinations (open eye visuals and closed eye visuals); illusions; difficulty focusing; synaesthesias. b. Psychic effects: mood alterations (from ecstatic euphoria to panic); time distortion; thought alterations (difficulty concentrating, strange concepts, ideas, or connections, increases in creativity); dreamlike feelings; depersonalization; the sense that awareness is ‘expanded’. c. Somatic effects: dizziness; tremors; nausea; drowsiness; blurred vision.

[0058] The terms ‘psychedelic state’, and 'hallucinogenic state' are used interchangeably herein and are characterized as set out above.

[0059] The relative prominence of particular effects can be strongly dependent on the specific psychedelic compound, the dosage, and the setting in which the drug is used. However, with psilocybin and psilocin (and derivatives or crystals forms thereof), the psychedelic state is characterized by an unconstrained form of cognition in which the stream of conscious experience appears more fluid and dynamic, with novel neural states being explored by the subject.

[0060] In some embodiments, induction of the psychedelic state in the subject marks the start of a therapeutic window, which is the time during which psychological support is most effective.

[0061] The psychedelic state can be assessed subjectively, for example by the therapist providing psychological support. In some embodiments, entry into the psychedelic state and / or monitoring of the duration of the psychedelic state uses a conventional technique fornon-invasive measurement of brain activity such as electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), optoencephalography (OEG). Preferably, EEG is used.

[0062] Psychological support is provided to the subject before, during or after induction of the psychedelic state. In the context of the methods described herein, psychological support is any form of support that is aimed at helping the subject to enhance their mental health and their cognitive, emotional and behavioural well-being. Typically, psychological support is provided by a therapist, psychiatrist, or other suitably qualified healthcare professional and preferably by a therapist who has been specifically trained on the administration of psychedelics.

[0063] In some embodiments the methods described herein involve the provision of psychological support after induction of the psychedelic state and after the subject has exited form the psychedelic state. In these embodiments the psychological support can be provided as an alternative, or in addition to psychological support provided while the subject is in a psychedelic state.

[0064] In some embodiments the psychological support is cognitive behavioural therapy (CBT). The cognitive behavioural model for treating IBS focuses primarily on(a) psychoeducation about the stress response and its relationship to Gl symptoms;(b) Building insight into cognitive and behavioral responses to IBS symptoms and / or fear of symptoms; and(c) Modifying those responses to decrease distress related to IBS and decrease physical reactivity to stress.

[0065] In other embodiments the psychological support is hypnotherapy. In this context, the hypnotherapy focuses post-hypnotic suggestions on the health of the gastrointestinal tract. There are currently two available standardized hypnotherapy protocols for IBS: the Manchester Approach and the North Carolina Protocol. Both are known in the art and are scripted, gut-directed hypnotherapy protocols.

[0066] In other embodiments the psychological support is mindfulness-based therapy (MBT) which is a form of treatment that uses meditation and relaxation to foster awareness and acceptance of the present moment. This approach requires individuals to practice noticing and observing details about their surroundings without passing judgment or reacting to triggers.

[0067] In some embodiments the cognitive behavioural therapy (CBT) concepts are based upon a self-guided approach and includes education regarding one or more of:• The “mind-gut” connection; stress and its relationship to Gl symptoms• Self-monitoring of stressful situations associated with Gl symptoms• Muscle relation exercises, body scanning, and diaphragmatic breathing• Learning to identify and change negative thoughts, e.g., catastrophizing• Modifying core beliefs such as perfectionism that fuel threatening cognitions• Formal training in problem solving and coping

[0068] Hypnotherapy can be delivered via an app in the home. Gut-directed hypnosis builds upon the mental and muscle relaxation components of the CBT program outlined above to use imagery that symbolizes the Gl tract, such as a river flowing smoothly, to gain control of inner physiologic phenomena.

[0069] Given the high levels of trauma experienced by patients with IBS the psychological support can incorporate elements of somatic experiencing, a therapy that encourages “bottom up” sensation-focused processing of trauma (as opposed to “top down” or cognitively driven approaches). Somatic experiencing aims to generate corrective interoceptive, visceral experiences that counteract the feelings of overwhelm and helplessness common to both patients with IBS and patients with trauma. Alongside this focus on bodily sensations as a manifestation of trauma, subjects will be provided education about the benefits of traditional meditative movement (e.g., yoga and t’ai chi) and cardiorespiratory exercise on IBS symptoms.

[0070] For subjects with IBS (e.g. IBS-D, IBS-C, or IBS-M), administration of a psychedelic according to the methods described herein improves one or more symptoms of IBS compared to the symptoms as experienced during a baseline period before administration of the psychedelic.

[0071] The baseline period may be any period suitable to establish a consistent picture of the symptoms experience by the subject. A suitable baseline period can be at least 3 days, for example 3 days, 4 days, 5 days, 6 days, 1 week, two weeks or three weeks.

[0072] In some embodiments administration of a psychedelic to a subject with IBS according to the methods described herein improves one or more symptoms of IBS experience by the subject, i.e. resolution of symptoms or a reduction in the frequency and / or severity of symptoms. The improvement can be assessed using a periodic (e.g. daily, every 2-3 days or weekly) global assessment of relief of overall IBS symptoms starting on the datethe psychedelic is first administered. The global assessment of relief of overall IBS symptoms is evaluated by taking all IBS symptoms experienced by the subject into consideration and comparing these with their symptoms in the baseline period.

[0073] For example, each symptom can be scored for the global assessment of relief of overall IBS as follows.0=completely relieved1=considerably relieved2=somewhat relieved3=unchanged4=worsened

[0074] Alternatively, or in addition a subject with IBS who is treated according to the methods described herein will exhibit less severe self reported abdominal discomfort or pain. This can be assessed using a periodic (e.g. daily, every 2-3 days or weekly) assessment (ether separately or as part of the global assessment mentioned above) of abdominal discomfort or pain starting on the date the psychedelic is first administered. The assessment takes into consideration all episodes of abdominal discomfort or pain reported by the subject and compares these to the episodes experienced by the subject in the baseline period.

[0075] For example, abdominal discomfort or pain can be scored as follows.0=completely relieved1 considerably relieved2=somewhat relieved3=unchanged4=worsened

[0076] In some embodiments subjects with IBS who are treated according to the methods described herein will exhibit an improvement of abnormal bowel habits compared to bowel habit in the baseline period. The improvement can be assessed using a periodic (e.g. daily) assessment of bowel habits starting on the date the psychedelic is first administered. Bowel habits are evaluated by taking all bowel movements into consideration and comparing these with bowel movements prior to treatment commencing. In this context, an abnormal bowel movement is any bowel movement of the subject that fits the description of types 1, 2, 5, 6, or 7 in the Bristol Stool Chart. An abnormal bowel movement can also be one that isinvoluntary, accompanied by a sudden sense of urgency, infrequent (i.e. less than once every three days), too frequent (i.e. more than twice per day), involves straining or pain.

[0077] Abnormal bowel movements can be scored as follows.0=completely relieved1 considerably relieved2=somewhat relieved3=unchanged4=worsened

[0078] For IBS-C, stool frequency as measured by number of complete spontaneous bowel movements (CSBMs) per week improves compared to the baseline period, that is increase compared to the number of CSBM's before treatment.

[0079] In some embodiments subjects with IBS, particularly those with IBS-D, who are treated according to the methods described herein exhibits an improvement in stool form (appearance) according to the Bristol Stool Chart compared to stool form in the baseline period. The Bristol Stool Chart ( Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920-924) is a reliable, accurate and frequently used chart that categorizes stools into one of seven stool types ranging from type 1 (hard lumps) to type 7 (watery diarrhea). Type 1-2 indicate constipation, types 3-4 are ideal stools as they are easier to pass, and types 5-7 are indicative of diarrhoea and / or urgency.

[0080] The Bristol Stool Scale has been validated as a reproducible measure of intestinal transit and stool form and is therefore in common use to assess stool form in several gastrointestinal disorders including IBS.

[0081] In this embodiment treated subjects record the stool form at every defecation. Over a period of time (for example one day, two days, three days, four days, five days, six days or more) an improvement is defined as a greater proportion of defecations having stool forms of type 3-4 compared to the same patient before treatment.

[0082] In some embodiments administration of a psychedelic according to the methods described herein improves the frequency of bowel movements, urgency of bowel movements, and / or the feeling of incomplete bowel movement.

[0083] The psychedelic compounds, salts thereof, co-crystals or crystal forms described herein may be administered as a formulation or composition comprising a pharmaceutically effective amount of the compound, in association with one or more pharmaceuticallyacceptable excipients including carriers, vehicles and diluents, chemical stabilizers such as anti-oxidants. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dosage form such as a solution or suspension suitable for parenteral administration such as by intravenous, intramuscular, intradermal, or subcutaneous, nasal or buccal application.

[0084] Excipients can include, by way of illustration and not limitation, diluents, wetting agents, polymers, lubricants, glidants, stabilizers, and substances added to improve appearance of the composition. Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low melting wax, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials. Examples of excipients and their use is described in Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0085] The compounds and pharmaceutical compositions of the invention may be formulated for injectable, nasal, parenteral, subcutaneous, intravenous, or intramuscular delivery. Non-limiting examples of particular formulation types include powders, granules, injectables, ampoules, vials, ready-to-use solutions, suspensions, or lyophilized materials.

[0086] For parenteral administration, including intravenous, intramuscular, or subcutaneous, administration, fluid unit dosage forms may be prepared by combining the psychedelic and a sterile vehicle, typically a sterile aqueous solution which is preferably isotonic with the blood of the subject. Depending on the vehicle and concentration used, the psychedelic may be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the psychedelic may be dissolved in saline (e.g. sterile saline), or water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition may be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder may then besealed in the vial and an accompanying vial of water for injection or other suitable liquid such as sterile saline may be supplied to reconstitute the liquid prior to use.

[0087] The total liquid volume before lyophilization can be less, equal to, or more than, the final reconstituted volume of the lyophilized formulation. The lyophilization process is well known to those of ordinary skill in the art, and typically includes sublimation of water from a frozen formulation under controlled conditions. Lyophilized formulations typically can be stored at a wide range of temperatures. For example, lyophilized formulations may be stored below 25°C, for example, refrigerated at 2-8°C, or at room temperature (e.g., approximately 25°C). Preferably, lyophilized formulations are stored below about 25°C, more preferably, at about 20°C; below about 4°C; or below about 0°C.

[0088] Lyophilized formulations are preferably reconstituted with a solution consisting primarily of water (e.g., USP WFI, or water for injection), bacteriostatic water (e.g., USP WFI with 0.9% benzyl alcohol), or 0.9% saline solution, preferably 0.9% saline solution is used. Alternatively, solutions comprising buffers and / or excipients and / or one or more pharmaceutically acceptable carriers may be used. The liquid that is to undergo freeze- drying or lyophilization preferably comprises all components desired in a final reconstituted liquid formulation.

[0089] In some embodiments, there is provided a kit for use in the methods, the kit comprising the lyophilized formulation and optionally a solution for reconstitution of the lyophilized formulation and instructions for use.Combination therapy

[0090] The terms 'combination therapy' or 'adjunct therapy' in defining use of a psychedelic compound (e.g. psilocin or psilocybin) and one or more other pharmaceutical agents, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations of each agent.

[0091] In some embodiments a psychedelic compound can be used with at least one additional therapeutic agent such as a non-steroidal anti-inflammatory, prokinetic, laxative, antispasmodic, analgesic, tricyclic antidepressant, selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, a non-absorbable antibiotic (such as rifamixin), 5-HT3 receptor antagonist, 5-HT4 receptor agonists, opioid receptor modulator, guanylate cyclase 2C agonist, or a chloride channel-2 agonist. Examples of suitable prokinetic drugsinclude bethanechoil, benzamide, cisapride, comperidone, itopride, mosapride, metoclopramide, prucalopride, renzapride, tegaserod, mitemcinal, levosulpiride, cinitapride, and linaclotide.

[0092] Examples of suitable antispasmodics include alverine citrate, simethicone, mebeverine, otolinium bromide, pinaverium bromide, phloroglucinol, hyoscine butylbromide, hyoscyamine, dicyclomine, trimebutine, and peppermint oil.

[0093] Examples of suitable analgesics include clonidine, gabapentin and pregabalin.

[0094] Examples of suitable non-steroidal anti-inflammatory agents include naproxen, ibuprofen, diclofenac, ketorolac, meloxicam, indomethacin, nabumetone, oxaprozin, piroxicam, sulindac, tolmetin, mefenamic acid, etodolac, ketoprofen, flurbiprofen, fenoprofen.

[0095] Examples of suitable tricyclic antidepressants include amitriptyline, nortriptyline, imipramine, and desipramine.

[0096] Examples of suitable selective serotonin reuptake inhibitors include citalopram, fluoxetine, paroxetine, and sertraline.

[0097] Examples of suitable serotonin-norepinephrine reuptake inhibitors include desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine.

[0098] A suitable non-absorbable antibiotic is rifaximin.

[0099] Suitable 5-HT3 receptor antagonists include odansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, alsoteron, cilansetron. Preferably the 5-HT3 receptor antagonist is alsoteron or odansetron.

[0100] Suitable 5-HT4 receptor agonists include cisapride, mosapride, prucalopride, renzapride, tegaserod, zacopride, metoclopramide, sulpiride, or naronapride.

[0101] Suitable opioid receptor modulator include asimadoline, eluxadoline, loperamide. In some embodiments opioid receptor modulators such as eluxadoline are particularly suitable for subjects with IBS-D.

[0102] Suitable guanylate cyclase 2C agonists include linaclotide and plecanatide. In some embodiments guanylate cyclase 2C agonists are particularly suitable for subjects with IBS- C.

[0103] Suitable chloride channel-2 agonists include prostones such as lubiprostone. In some embodiments chloride channel-2 agonists such as lubiprostone are particularly suitable for subjects with IBS-C.

[0104] Other suitable therapeutic agents include bile acid binders as bile acid sequestration may relieve the cholerrheic effect of bile acids. Colesevelam and cholestyramine are examples of suitable bile acid sequestration agents.

[0105] In some embodiments mast cell stabilizers such as disodium cromoglycate, ketotifen, and 5-aminosalicylic acid (5-ASA) can be used in combination with a psychedelic compound.

[0106] In some embodiments a psychedelic compound can be used with at least one serotonin synthesis inhibitors, spherical carbon adsorbent, benzodiazepine receptor modulator, peripheral kappa-opioid agonist or a 5-HT3 antagonist.

[0107] Examples of suitable serotonin synthesis inhibitors include telotristat (LX-1031), a tryptophan hydroxylase inhibitor that reduces local 5-HT synthesis and 5- hydroxyindoleacetic acid (5-HIAA) excretion. Unlike previous 5-HT inhibitors, LX-1031 does not cross the blood-brain barrier, thereby reducing the risk of depression and central nervous system disorders. It also improves pain and stool consistency.

[0108] AST- 120 is a preparation of spherical carbon particles that adsorb bacterial toxins, inflammatory mediators and bile acid products and prevent them from entering systemic circulation.

[0109] An example of a suitable benzodiazepine receptor modulator is dextofisopam which binds to benzodiazepine receptors in the brain, without a sedating effect. In animal studies, it reduced colonic motility and visceral sensitivity in response to stress.

[0110] An example of a suitable peripheral kappa-opioid agonist is asimadoline, a kappaopioid agonist, which can reduce pain, urgency and stool frequency in IBS patients.

[0111] A suitable 5-HT3 antagonist is alosteron, ondansetron or ramosetron, a selective 5- HT3 antagonist that increases self-reported relief of IBS symptoms. Constipation occurs in roughly 5 percent of subjects treated with ramosetron, this is less than the rate observed with alosetron.

[0112] Combination regimens may involve the active agents being administered together, sequentially, or spaced apart as appropriate in each case. Combinations of active agents including compounds of the invention may be synergistic.

[0113] The co-administration of compounds of the invention may be effected by the compounds being in the same unit dose as another active agent, or the compounds and one or more other active agent(s) may be present in individual and discrete unit doses administered at the same, or at a similar time, or at different times according to a dosingregimen or schedule. Sequential administration may be in any order as required and may require an ongoing physiological effect of the first or initial compound to be current when the second or later compound is administered, especially where a cumulative or synergistic effect is desired.

[0114] For example, it is anticipated that when the methods described herein are used to treat IBS administration of an antispasmodic medication (such as dicyclomine or hyoscine) to reduce cramping may contribute to providing a positive environment that can be reinforced during the psychedelic state. That is, in some embodiments there is a “pretreatment period” to prepare the subject for administration of the compound to enhance the impact of the compound (e.g. psilocin or psilocybin) and to induce a more lasting effect which may otherwise be undermined by painful symptoms of the gut-brain interaction disorder.Psychedelic Compounds

[0115] Psychedelic compounds suitable for use in the methods described herein include any one or more of psilocin (4-hydroxy-N,N-dimethyltryptamine), or psilocybin ([3-(2- dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate), a derivative thereof, a crystalline form thereof, a cocrystal thereof, and a pharmaceutically acceptable salt thereof.

[0116] For example, in one embodiment the psychedelic compound is selected from 4 hydroxytryptamine, [3-(2-methylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, 4- hydroxy-N-methyltryptamine, [3-(aminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, [3-(2- trimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, and 4-hydroxy-N,N,N- trimethyltryptamine, a crystalline form thereof, a cocrystal thereof, and a pharmaceutically acceptable salt thereof.

[0117] Psilocybin and psilocin derivatives that are useful include those where the hydroxyl group is modified, or the methyl groups of the terminal amine nitrogen have been modified. Example hydroxyl group substituents include alkyl and aryl ethers and esters, for example methoxy and ethoxy ethers and acetyl esters, halogens including fluoro-, chloro-, and bromo-substituents, and thio groups such as methylthio or benzothio. Exemplary nitrogen group substituents include one or both methyl groups substituted with ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, amyl or allyl groups and the N-trimethyl analogs. The corresponding phosphate esters, namely psilocybin derivatives, may also prove useful, as may derivatives where one or more hydrogen atom is replaced by fluorine, chlorine, or bromine.

[0118] In some embodiments a pharmaceutically acceptable salt of the psychedelic compound is used in the methods. The term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the art.

[0119] Suitable salts include any pharmaceutically acceptable salt that can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, boric, sulfamic, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, butyric, glycolic, gluconic, lactic, mucic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, edetic, hydroxymaleic, pyruvic, alkyl sulfonic, arylsulfonic, aspartic, glutamic, benzoic, palmitic, oleic, lauric, valeric, benzenesulfonic, oxalic, anthranilic, mesylic, methanesulfonic, toluenesulfonic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, pantothenic, tannic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxybutyric, galactaric, and galacturonic acids. Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Alternatively, suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, ammonium salts, alkylamonnium, quaternary salts such as tetramethylammonium salt, amino acid addition salts such as salts with glycine and arginine. Also, basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl and diethyl sulfate. Metal salts can be prepared by reaction of a psychedelic with a metal hydroxide. An acid salt can be prepared by reacting an appropriate acid with a psychedelic.

[0120] In a preferred embodiment, a salt of the psychedelic compounds is used, for example a benzenesulfonate (besylate), hydrochloride, fumarate, maleate, picrate, oxalate, tartrate, and sulfate salt, which are typically more stable. Preferably the salt is a besylate salt.

[0121] Suitable derivatives of the psychedelic compound include: 4-acetoxy-N,N- dimethyltryptamine (4-AcO-DMT or O-acetyl psilocin) the acetylated form of the psilocin (4- OH-DMT) a compound is a potential prodrug of psilocin (as are other 4-alkyl-esters), more stable than psilocin, and has a longer shelf life; 4-acetoxy-N-methyl-N-ethyltryptamine (4- AcO-MET), a psilocin analog substituted at R4 of its indole heterocycle with an acetoxy (AcO or CH3COO-) functional group which also contains a methyl group and an ethyl chain bound to the terminal amine nitrogen of its tryptamine backbone. 4-AcO-MET is an acetate ester analog of 4-OH-MET and a N-substituted ethyl homolog of 4-AcO-DMT; 4-acetoxy- N,N-diethyltryptamine (4-AcO-DET); 4-acetoxy-N-methyl-N-propyltryptamine (4-AcO-MPT); 4-acetoxy-N-methyl-N-isopropyltryptamine (4-AcO-MIPT); 4-acetoxy-N,N-dipropyltryptamine (4-AcO-DPT) and 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DI PT); 4-hydroxy-N-methyl- N-ethyltryptamine (4-OH-MET, metocin, or methylcybin), a 4-hydroxy N-substituted structural analog of psilocin and with a methyl and an ethyl group bound to the terminal amine nitrogen of the tryptamine structure; 4-hydroxy-N-methyl-N-propyltryptamine (4-OH- MPT); 4-hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MI PT); 4-hydroxy-N,N- diethyltryptamine (4-OH-DET); 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT); 4-hydroxy- N,N-diisopropyltryptamine (4-OH-DI PT); and 4-hydroxy-N,N-diallyltryptamine (4-OH-DALT); analogs where the 4-OH group has been removed, such as N,N-dimethyltryptamine (DMT), N-methyl-N-ethyltryptamine (MET), N-methyl-N-propyltryptamine (MPT), N,N- diethyltryptamine (DET), N,N-dipropyltryptamine (DPT), N,N-isopropyltryptamine (DIPT), N- methyl-N-isopropyltryptamine (MIPT), a-methyltryptamine (AMT), N-ethyl-N- isopropyltryptamine (EIPT), N-methyl-N-butyl-tryptamine (MBT) or analogs substituted at other positions such as N,N-dimethyl-5-hydroxytryptamine (5-OH-DMT or bufotenine), 5- methoxy-a-methyltryptamine (5-MeO-aMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT), 5-methoxy-N,N-diethyltryptamine (5-MeO-DET), 5-methoxy-N,N-dipropyltryptamine (5-MeO-DPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N-ethyl-N- isopropyltryptamine (5-MeO-EI PT), 2,a-dimethyltryptamine (2,a-DMT), a,N- dimethyltryptamine (a,N-DMT), a-ethyltryptamine (a-ET), 2-methyl-N,N-dimethyltryptamine (2-Me-DMT), 2-methyl-N,N-diethyltryptamine (2-Me-DET), 1-methylpsilocin and ibogaine (a complex tryptamine).

[0122] In one embodiment, the psychedelic compound is psilocybin. Psilocybin is a naturally occurring psychedelic compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms. Once administered to a subject, psilocybin is metabolized by endogenous alkaline phosphatase to psilocin the active metabolite which crosses the blood brain barrier to induce the psychedelic state. In a preferred embodiment, the psychedelic is psilocin.

[0123] Psilocybin is also known as [3-(2-dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, and given the CAS number 520-52-5. Psilocin (also known as 4-hydroxy-N,N- dimethyltryptamine (4- HO- DMT), psilocine, psilocyn, or psilotsin) and given the CAS number 520-53-6.

[0124] In some embodiments, equimolar amounts of a psilocin or psilocybin derivative may be used in place of psilocybin and / or psilocin, or amounts producing equivalent functional effects may be used.

[0125] In some embodiments a co-crystal comprising the psychedelic may be used. Cocrystals are multicomponent systems in which two components, an active pharmaceutical ingredient and a conformer, are present in stoichiometric ratio and bonded together in the crystal lattice by hydrogen bonding, TT-TT interactions, and van der Waals forces. In some embodiments the conformer and the active can be bonded with a non-covalent bond such as a halogen bond.

[0126] Psilocybin and psilocin cocrystals useful in the methods described herein comprise at least one conformer, which can form supramolecular synthons with the psilocybin molecule. The formation of these supramolecular synthons allows cocrystals to form.

[0127] In one embodiment, the coformer has a carboxamide moiety, which can form an acid amine heterosynthon with the nitrogen atoms in the psilocybin or psilocin molecule. In another embodiment, the coformer molecule forms heterosynthons with the phosphate moiety of psilocybin.

[0128] In one embodiment, a crystalline form of the psychedelic compound is useful. For example, a crystalline form of a pharmaceutically acceptable salt of psilocin or psilocybin is a cocrystal comprising a coformer. The coformer may be any pharmaceutically acceptable coformer known in the art. Preferably, the coformer is arginine, acetylsalicylic acid, glucose, nicotinic acid, aconitic acid, glutamic acid, oxalic acid, adipic acid, glutaric acid, proline, 4- aminosalicylic acid, glycine, propyl gallate, ascorbic acid, glycolic acid, pyroglutamic acid, benzoic acid, hippuric acid, saccharin, camphoric acid, 1-hydroxy-2-naphthoic acid, salicylic acid, capric acid, ketoglutaric acid, sebacic acid, cinnamic acid, lysine, sodium lauryl sulfate,citric acid, magnesium bromide, sorbic acid, cyclamic acid, maleic acid, succinic acid, ethyl maltol, malic acid, tartaric acid, ethyl paraben, malonic acid, urea, fructose, maltol, vanillic acid, fumaric acid, mandelic acid, vanillin, gallic acid, methyl paraben, zinc chloride, gentisic acid, nicotinamide or ethyl acetate. Preferably, the coformer is selected from the group consisting of arginine, lysine, methyl paraben, nicotinamide and ethyl acetate. Preferably, the coformer is ethyl acetate. According to a first aspect, the invention provides a crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N- dimethyltryptamine), or a cocrystal of psilocin (4-hydroxy-N,N-dimethyltryptamine) and a coformer. In one embodiment the pharmaceutically acceptable salt is an acid.

[0129] The acid or coformer may be selected from one or more of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, arginine, lysine, methyl paraben, nicotinamide and ethyl acetate.

[0130] In one embodiment the acid with psilocin is benzenesulfonic acid. The crystalline form may be Besylate Form A.

[0131] The psilocin besylate Form A may exhibit XRPD (X-ray power diffraction) peaks at about 15.44° 20 ± 0.20, 18.33° 20 ± 0.20, and 25.41° 20 ± 0.20; or exhibit peaks at about 14.73° 20 ± 0.20, 15.44° 20 ± 0.20, 18.33° 20 ± 0.20, 22.59° 20 ± 0.20, and 25.41° 20 ± 0.20; or exhibit peaks at about 11.72° 20 ± 0.20, 12.47° 20 ± 0.20, 13.49° 20 ± 0.20, 14.73° 20 ± 0.20, 15.44° 20 ± 0.20, 18.33° 20 ± 0.20, 20.62° 20 ± 0.20, 20.99° 20 ± 0.20, 21.77° 20 ± 0.20, 22.25° 20 ± 0.20, 22.59° 20 ± 0.20, 23.22° 20 ± 0.20, 23.71° 20 ± 0.20, 24.10° 20 ± 0.20, and 25.41° 20 ± 0.20.

[0132] The psilocin besylate Form A may alternatively exhibit XRPD (X-ray power diffraction) peaks at about 15.58° 20 ± 0.20, 18.48° 20 ± 0.20, and 25.60° 20 ± 0.20; or exhibit peaks at about 14.87° 20 ± 0.20, 15.58° 20 ± 0.20, 18.48° 20 ± 0.20, 22.74° 20 ± 0.20, and 25.60° 20 ± 0.20; or exhibit peaks at about 11.85° 20 ± 0.20, 12.61° 20 ± 0.20,13.64° 20 ± 0.20, 14.87° 20 ± 0.20, 15.58° 20 ± 0.20, 18.48° 20 ± 0.20, 20.79° 20 ± 0.20,21.13° 20 ± 0.20, 21.94° 20 ± 0.20, 22.38° 20 ± 0.20, 22.74° 20 ± 0.20, 23.39° 20 ± 0.20,23.87° 20 ± 0.20, 24.26° 20 ± 0.20, and 25.60° 20 ± 0.20.

[0133] In one embodiment the psilocin Besylate Form A may exhibit XRPD peaks at about 7.69° 20 ± 0.20, 10.26° 20 ± 0.20, 10.96° 20 ± 0.20, 11.72° 20 ± 0.20, 12.47° 20 ± 0.20, 12.84° 20 ± 0.20, 13.49° 20 ± 0.20, 14.73° 20 ± 0.20, 15.44° 20 ± 0.20, 16.18° 20 ± 0.20,18.33° 20 ± 0.20, 19.04° 20 ± 0.20, 19.68° 20 ± 0.20, 20.62° 20 ± 0.20, 20.99° 20 ± 0.20,21.77° 20 ± 0.20, 22.25° 20 ± 0.20, 22.59° 20 ± 0.20, 23.22° 20 ± 0.20, 23.71° 20 ± 0.20,24.10° 20 ± 0.20, 25.15° 20 ± 0.20, 25.41° 20 ± 0.20, 25.65° 20 ± 0.20, 26.29° 20 ± 0.20,26.76° 20 ± 0.20, 27.72° 20 ± 0.20, 27.99° 20 ± 0.20, 28.67° 20 ± 0.20, 28.93° 20 ± 0.20,29.63° 20 ± 0.20, 30.43° 20 ± 0.20, 30.76° 20 ± 0.20, 31.15° 20 ± 0.20, 31.77° 20 ± 0.20,32.13° 20 ± 0.20, 32.94° 20 ± 0.20, 33.65° 20 ± 0.20, 34.94° 20 ± 0.20, 35.69° 20 ± 0.20, and 36.49° 20 ± 0.20.

[0134] In al alternate embodiment the psilocin Besylate Form A may exhibit XRPD peaks at about 7.78° 20 ± 0.20, 11.85° 20 ± 0.20, 12.61° 20 ± 0.20, 13.64° 20 ± 0.20, 14.87° 20 ± 0.20, 15.58° 20 ± 0.20, 16.00° 20 ± 0.20, 18.48° 20 ± 0.20, 19.83° 20 ± 0.20, 20.79° 20 ±0.20, 21.13° 20 ± 0.20, 21.94° 20 ± 0.20, 22.38° 20 ± 0.20, 22.74° 20 ± 0.20, 23.38° 20 ±0.20, 23.87° 20 ± 0.20, 24.26° 20 ± 0.20, 25.28° 20 ± 0.20, 25.60° 20 ± 0.20, 26.92° 20 ±0.20, 27.99° 20 ± 0.20, 20.08° 20 ± 0.20, 31.28° 20 ± 0.20, 33.88° 20 ± 0.20, 35.13° 20 ±0.20, 35.90° 20 ± 0.20, 36.70° 20 ± 0.20 and 37.39° 20 ± 0.20

[0135] In another embodiment the acid with psilocin is butyric acid. The crystalline form may be Butyrate Form A.

[0136] The psilocin Butyrate Form A may exhibit XRPD (X-ray power diffraction) peaks at about 13.24° 20 ± 0.20, 15.34° 20 ± 0.20, and 15.88° 20 ± 0.20; or may exhibit peaks at about 13.24° 20 ± 0.20, 15.34° 20 ± 0.20, 15.88° 20 ± 0.20, 16.28° 20 ± 0.20, 20.95° 20 ± 0.20, and 27.79° 20 ± 0.20; or may exhibit XRPD (X-ray power diffraction) peaks at about 9.33° 20 ± 0.20, 9.96° 20 ± 0.20, 10.66° 20 ± 0.20, 13.24° 20 ± 0.20, 15.34° 20 ± 0.20, 15.88° 20 ± 0.20, 16.28° 20 ± 0.20, 17.80° 20 ± 0.20, 20.95° 20 ± 0.20, 21.98° 20 ± 0.20, 22.32° 20 ± 0.20, 23.31° 20 ± 0.20, 24.61° 20 ± 0.20, and 27.79° 20 ± 0.20.

[0137] In one embodiment the psilocin Butyrate Form A may exhibit XRPD peaks at about 9.33° 20 ± 0.20, 9.96° 20 ± 0.20, 10.66° 20 ± 0.20, 12.96° 20 ± 0.20, 13.24° 20 ± 0.20, 14.36° 20 ± 0.20, 15.34° 20 ± 0.20, 15.88° 20 ± 0.20, 16.28° 20 ± 0.20, 17.80° 20 ± 0.20,18.36° 20 ± 0.20, 18.75° 20 ± 0.20, 18.97° 20 ± 0.20, 19.63° 20 ± 0.20, 20.01° 20 ± 0.20,20.35° 20 ± 0.20, 20.95° 20 ± 0.20, 21.44° 20 ± 0.20, 21.98° 20 ± 0.20, 22.32° 20 ± 0.20,22.80° 20 ± 0.20, 23.31° 20 ± 0.20, 23.77° 20 ± 0.20, 24.41° 20 ± 0.20, 24.61° 20 ± 0.20,25.46° 20 ± 0.20, 25.60° 20 ± 0.20, 26.22° 20 ± 0.20, 26.67° 20 ± 0.20, 27.79° 20 ± 0.20, and 29.07° 20 ± 0.20.

[0138] In another embodiment the acid with psilocin is gentisic acid. The crystalline form is Gentisate Form A.

[0139] The psilocin Gentisate Form A may exhibits XRPD peaks at about 15.80° 20 ± 0.20, 16.51° 20 ± 0.20, and 23.98° 20 ± 0.20;, or may exhibits XRPD peaks at about 15.52° 20 ± 0.20, 15.80° 20 ± 0.20, 16.51 ° 20 ± 0.20, 23.98° 20 ± 0.20, and 24.74° 20 ± 0.20; or mayexhibit XRPD peaks at about 12.77° 20 ± 0.20, 14.08° 20 ± 0.20, 15.52° 20 ± 0.20, 15.80° 20 ± 0.20, 15.98 ± 0.20, 16.51° 20 ± 0.20, 17.30° 20 ± 0.20, 18.58° 20 ± 0.20, 20.95° 20 ± 0.20, 21.64° 20 ± 0.20, 23.38° 20 ± 0.20, 23.98° 20 ± 0.20, 24.74° 20 ± 0.20, 25.19° 20 ± 0.20, 27.81° 20 ± 0.20, 28.41° 20 ± 0.20, and 28.80° 20 ± 0.20.

[0140] In one embodiment psilocin Gentisate Form A and exhibits XRPD peaks at about 7.74° 20 ± 0.20, 9.01° 20 ± 0.20, 11.01° 20 ± 0.20, 12.29° 20 ± 0.20, 12.77° 20 ± 0.20,13.15° 20 ± 0.20, 13.80° 20 ± 0.20, 14.08° 20 ± 0.20, 15.52° 20 ± 0.20, 15.80° 20 ± 0.20,15.98° 20 ± 0.20, 16.11° 20 ± 0.20, 16.51° 20 ± 0.20, 17.30° 20 ± 0.20, 18.07° 20 ± 0.20,18.58° 20 ± 0.20, 19.13° 20 ± 0.20, 19.39° 20 ± 0.20, 19.56° 20 ± 0.20, 20.95° 20 ± 0.20,21.64° 20 ± 0.20, 22.18° 20 ± 0.20, 22.45° 20 ± 0.20, 23.03° 20 ± 0.20, 23.38° 20 ± 0.20,23.98° 20 ± 0.20, 24.74° 20 ± 0.20, 24.95° 20 ± 0.20, 25.19° 20 ± 0.20, 25.71° 20 ± 0.20,26.08° 20 ± 0.20, 26.47° 20 ± 0.20, 27.28° 20 ± 0.20, 27.81° 20 ± 0.20, 28.41° 20 ± 0.20,28.80° 20 ± 0.20, 30.13° 20 ± 0.20, 30.66° 20 ± 0.20, 31.90° 20 ± 0.20, 32.16° 20 ± 0.20,32.57° 20 ± 0.20, 33.37° 20 ± 0.20, 33.75° 20 ± 0.20, 34.77° 20 ± 0.20, 35.29° 20 ± 0.20,36.25° 20 ± 0.20, and 36.80° 20 ± 0.20.

[0141] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.ExamplesExample 1 : A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of Oral Psilocybin Administration in Concert with Psychotherapy Among Adult Patients with Irritable Bowel Syndrome

[0142] The pressing need for effective irritable bowel syndrome (IBS) treatments led to investigating a psilocybin therapy as a treatment for IBS. An overview of the objectives and endpoints is presented in Table 1.Table 1: Clinical trial detailsAEs=adverse events; BP=blood pressure; ECG=electrocardiogram; EEG=electroencephalogram; fMRI=functional magnetic resonance imaging; GABA=gamma aminobutyric acid;Glx=glutamine+glutamate; HR=heart rate; I BS= Irritable Bowel Syndrome; IBS-C=IBS with Constipation; IBS-D=IBS with Diarrhea; IBS-M=IBS mixed type; PD=pharmacodynamic; PROs=patient reported outcomes.Overall Design

[0143] Participants with IBS (all subtypes) and with no exclusionary co-morbid psychiatric or medical disorders will be enrolled in the study. This study comprises approximately a 28- day screening period (Days -28 to -1), 3 weeks for baseline and preparation (Days 1 to 18), a 2-dose administration period (Days 22 and 37 or days 22 and 43), integration (Days 23, 30, 38 and 45), the End of Therapy (EOT) visit (Day 52 [with last weekly average of worst daily pain score and weekly stool frequency and consistency for the 7 days immediately prior to EOT visit assessed for change from baseline]) and 3-, 6- and 12-month follow-up visits (Days 120, 204, 365).Brief Summary

[0144] Disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS), are prevalent, frequently disabling, and impose a major economic burden. IBS is defined by the Rome IV criteria as at least weekly abdominal pain that is associated with eating ordefecation. IBS is frequently comorbid with other pain syndromes such as migraine and fibromyalgia and is associated with mood disturbances including anxiety and depression. Current management of IBS is multidimensional, including behavioral therapy, exercise, and medication. However, current medications provide only modest benefit and carry significant side effect burden, leading many people with IBS to seek other alternatives.

[0145] Psilocybin-assisted therapy (PAT, or psilocybin delivered in concert with psychotherapy) is anticipated by the inventors to be a safe and effective treatment for symptoms associated with IBS. The United States Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for psilocybin in treatment-resistant depression and major depressive disorder. PAT and psilocybin therapy are generally safe and well-tolerated when conducted under controlled conditions. However, no clinical studies have explored psychedelic clinical benefits among people with IBS.Number of Participants

[0146] Participants are screened with the goal of enrolling up to 10 participants who will complete the double dose of psilocybin administered 2 weeks apart, the primary and secondary outcome measures, and complete the study and follow-up periods. It is anticipated that approximately equal groups of patients with IBS-C, IBS-D, and IBS-M are enrolled.Intervention Groups and Duration

[0147] This is an open-label study, and participants who meet the inclusion and exclusion criteria are eligible and invited to enroll. Participants receive two 25mg oral doses of psilocybin.

[0148] The total duration of the study for an individual participant from screening to last follow-up is approximately 12 months, and the primary endpoints are assessed within the first month after treatment. A Safety Review Committee (SRC) is responsible for the assessment of safety and to make recommendations regarding study progression. The SRC comprises the principal investigator, the study’s principal psychiatrist, one medically qualified sponsor representative (SRC Chair), and an independent biomedical professional with relevant experience and expertise. The SRC continually monitors safety and may recommend the following procedures to the sponsor, as appropriate:• continue the study as planned• continue the study with modifications of procedures, such as dose, safety monitoring, or other• suspend enrollment to further evaluate safety events (mandatory for any event that meets a Stopping Rule• terminate the study

[0149] A schedule of Activities is presented in Table 2.Table 2: Schedule of ActivitiesAE=adverse event; CMSI =Complex Medical Symptoms Inventory; (C-SSRS=Columbia Suicide Severity Rating Scale; ECG=Electrocardiogram; HADS=Hospital Anxiety and Depression Scale; IBS = Irritable Bowel Syndrome; IBS- SSS=Irritable Bowel Syndrome Severity Scoring System; PGI-C= Patient Global Impression of Change; Q=questionnaire; R4DQ = Rome IV Diagnostic Questionnaire for Functional Gastrointestinal Disorders in Adults; SAE=serious adverse event; SCID-5=Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders 5th Edition; SCID- 5-PD= Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders-5 for Personality Disorders; WOCBP=women of childbearing potential.Note: Assessments scheduled on a day of study drug administration should be performed prior to study drug dosing unless otherwise specified. a Informed consent must be obtained before any study-specific screening assessments are performed. Screening assessments are to be performed within 28 days preceding Dose 1 . b Complete blood count (CBC) and basic metabolic panel (BMP) are collected for all patients during screening. If the remainder of screening labs have not been checked within two years (CMP, CRP, ESR, Celiac studies, thyroid studies), they are re-collected during screening. c Participants should be supine and rested for at least 5 minutes before the ECG is recorded, d A urine pregnancy test is performed and results determined locally. (Pregnancy Testing) e Urine drug and breath alcohol testing is performed and results determined locally.(Urine / Drug Testing) f Includes heart rate, systolic and diastolic blood pressure preferably with an automated device. Participants should be supine and rested for at least 5 minutes in a quiet setting before testing. (Vital Signs) g ePRO stool frequency, consistency, and abdominal pain diary is to be completed daily, by the participant, on their phone and checked for completeness by study staff remotely For stool tracking (abdominal pain and frequency), patients fill out a survey on their phone daily reporting the last 24 hours for seven days prior to and including the visit day number (e g., the 3-month follow up visit at day 120 collect data from days 113-120.). (Patient Reported Outcomes) h All AEs and SAEs are to be recorded at the times indicated regardless off attribution. i The Monitor Rating Form is used by the same 2 therapists to provide ratings at the time of the dose and at end of therapy that focus on integration j Medical occurrences that begin before Baseline but after obtaining informed consent are recorded as medical history, not as AEs. k To be performed approximately 7 hours after dosing.1 Qualitative written assessment is to be completed at 3-month follow up only. m Participants wear an Apple Watch from collection of baseline measures until the end of the final deep phenotyping session. The Apple Watch generates ECG / HR data, from which heart rate variability is calculated. n Biomarkers include high-sensitivity CRP, ESR, WBC, TNF-a and IL-6, o fMRI section p EEG section

[0150] Considering the measures taken to minimize risk to participants in this study, the known and potential risks identified in association with psilocybin are justified by the anticipated benefits that may be afforded to participants with IBS.Overall Design

[0151] All participants must have IBS or have had IBS symptoms for at least a year and meet the Rome IV Criteria for IBS (any subtype.) Exclusion criteria include certain co- morbid psychiatric disorders (e.g., psychotic disorders, bipolar I or II disorder, substance use disorder), diagnosis of centrally mediated abdominal pain syndrome by Rome IV Criteria, history of a medically significant suicide attempt, and use of certain medications (e.g., anti-depressants).

[0152] All participants enrolled in the study are expected to receive two doses of psilocybin during in-center study intervention sessions.

[0153] “Active intervention” includes baseline deep phenotyping, preparation, study drug administration, integration, and EOT deep phenotyping.

[0154] Study visits may have visit “windows” as shown in the Schedule of Activities (SoA, Table 2).

[0155] The total duration of study participation for an individual participant is approximately 12 months, including screening, preparation, administration, integration, EOT, and follow-up.

[0156] The total planned duration of the entire study is expected to be 18 months.Screening Period (Visit 1, Day -28 to Trial Initiation)

[0157] Once candidates are pre-screened for interest and eligibility, they complete a screening visit in which the informed consent process is completed before any other procedures are assessed. When inclusion and exclusion criteria are confirmed, other assessments are completed as follows:• demographic and baseline characteristics• medical history• prior / concomitant medications• Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders 5thEdition (SCID-5) and SCID-5 for Personality Disorders (SCID-5-PD)• 12-lead electrocardiogram (ECG)• pregnancy test for women of childbearing potential (WOCBP)• urine drug and breath alcohol tests (breathalyzer)• vital signs• patient reported outcomes (Hospital Anxiety and Depression Scale [HADS], Rome IV Diagnostic Questionnaire for Functional Gastrointestinal Disorders in Adults [R4Q], Columbia Suicide Severity Rating Scale [C-SSRS])• Basic Metabolic Panel (BMP): Na+, K+, CI-, HCO3-, Ca++, Mg++, P, BUN, creatinine, glucose• Hematology: CBC with white cell differential and platelet count• If the remainder of screening labs have not been checked within two years (comprehensive metabolic panel including BMP as above with total bilirubin, albumin, ALT, AST, alkaline phosphatase, C-reactive protein (CRP), sedimentation rate (ESR), Celiac screen, TSH), they are re-collected during screening.

[0158] Any clinically significant abnormal laboratory findings for blood chemistry or hematology would be exclusionary from study participation.

[0159] After completing screening and enrollment, a two-week run-in period will commence during which patients will download to their phones a HIPAA-compliant application to collect electronic patient-reported outcomes (ePRO). This application will prompt participants daily to complete a stool diary, noting frequency, consistency, and abdominal pain. Completing at least 10 / 14 days of this tracking successfully is required for study entry.

[0160] Patients are also be given an Apple Watch and instructed to wear it around-the- clock, except during recharging of the device. The Apple Watch generates HR data, from which heart rate variability will be measured. Similarly to the ePRO application tracking requirements above, patients will be required to complete at least 10 / 14 days of heart rate tracking successfully for study entry.Baseline (Visit 2, Day 1)

[0161] Assessments on Day 1 are considered baseline assessments. On Day 1, participants undergo a rigorous pain phenotyping assessment (i.e. , deep phenotyping) as shown in Table 2). A validated battery of patient reported outcomes includes the following:• The Hospital Anxiety and Depression Scale is used to assess for comorbid anxiety and depression and describe their severity, if present. This tool is well-validated in populations with comorbid somatic illness. A HADS anxiety or depression subscore of 11 or greater indicates likely presence of the respective mood disorder.• The Rome IV Diagnostic Questionnaire for Functional Gastrointestinal Disorders in Adults (R4DQ) are international consensus guidelines, last updated in 2016 is used to characterize the existence of various DGBI, including IBS and its subtypes.• The IBS-Severity Scoring System (IBS-SSS) is used to generate a summative score incorporating measures of pain, distension, bowel dysfunction and quality of life / global well-being. The maximum (most severe) score is 500, with severe cases scoring >300.• The Visceral Sensitivity Index (VSI) is used to measure Gl-specific anxiety, including the constructs of worry, fear, vigilance, sensitivity, and avoidance.• The Life Events Checklist for DSM-5 (LEC-5) is used to assess past history of or exposure to trauma. Participants indicate how many of 16 potentially traumatic events (e.g., natural disaster, physical assault) they experienced personally or witnessed, as well as an additional item assessing any other very stressful event or experience. The number of events that participants indicate happened to them personally is summed, with scores potentially ranging from 0 to 17.• The Complex Medical Symptom Inventory (CMSI) is used to screen for chronic overlapping pain conditions, as other pain conditions commonly co-occur in IBS. Bloodwork is drawn for inflammatory biomarkers (High sensitivity C-Reactive Protein, ESR, WBC, TNF-a, and IL-6.) These biomarkers have been linked to IBS severity, particularly in IBS-D.

[0162] From this deep phenotyping session until the end of active intervention (28 days after psilocybin dosing session), participants complete a daily electronic pain and stool diary to evaluate abdominal pain level on a scale of 0 to10, on the Pain Intensity-Numeric Rating Scale (PI-NRS) and to track stool frequency and consistency according to the Bristol stool chart.

[0163] Patients also continue to wear their Apple Watch from collection of baseline measures until the end of therapy visit.

[0164] Patients additionally undergo an fMRI scan (1 hour) and EEG (45 minutes) during this visit.Preparation Period (Visits 3 and 4, Day 11 and Day 18)

[0165] Participants begin psychotherapy intervention, the structure of which has been used in previous PAT clinical trials. As with other PAT studies, discussions include information on the participant’s life history, current situation in life, as well as the participant’s understanding, expectations, and intentions for the psilocybin administration session. In brief, during the approximately 8 hours of preparatory therapy at Visits 3 and 4, participants develop rapport with two assigned therapists, learn about IBS, and build comfort and understanding around the physical space and what occurs in the dosing session.

[0166] Patients continue to wear their Apple Watch from collection of baseline measures until the end of therapy visit.PSILOCYBIN Administration Period (Visit 5, Day 22 and Visit 8, Day 37)

[0167] The procedures used during the administration period are consistent with those from other published studies of PAT. Participants are asked to eat a low-fat breakfast before reporting for their dosing sessions. Before administration of study drug, participants provide urine samples that are tested for drugs as well as for pregnancy, a breath alcohol test is also administered. All tests must be negative for participants to proceed. Participants also complete pre-session questionnaires and a brief interview with study personnel. The purpose of this brief interview is to assess if the session is contraindicated. If so, then that session will be postponed if possible.

[0168] Participants receive one dose of 25 mg of oral psilocybin on Day 22 and a second dose of 25mg oral psilocybin on day 37, ±3 days for each session. Psilocybin is administered in a comfortable setting under the guidance of the same two therapists from the preparation period. Participants have an in-person study visit following the resolution of the psychoactive effects of the psilocybin (as determined by the therapists in discussion with the participant) to ensure participant safety and comfort.

[0169] During the dosing session, which takes at least 8 hours, two therapists are present in the room and available to support participants’ physical and emotional needs. A study physician will be on call and within 5 minutes of the session room during the first 3 hours or until the peak effects of psilocybin have abated, and will remain available for the remainder of the course of the psilocybin dosing session if needed for consultation. During these sessions, participants are instructed to lie on a comfortable couch or bed, wear eyeshades, and listen to music through headphones, all of which are meant to enhance and encourage internal attention and reflection. Participants are encouraged by the therapist to direct their attention inward. Recumbent BP and HR is monitored until the drug effects have lessened. There is an automated external defibrillator located on site and a crash cart containing medicine and equipment for emergency resuscitation.

[0170] During the same period as the vital signs measurements, therapists also complete the monitor rating form, which includes questions about the presence / intensity of behavioral, signs, and reported symptoms, such as peacefulness, yawning, nausea / vomiting, quantity of speech, anxiety, sleepiness, crying, restlessness, visual changes, euphoria, and feelings of unreality. These sessions are video and audio recorded. After the study drug effects have subsided, participants complete questionnaires that assess the subjective experiences of the psilocybin dosing session, and the therapistscomplete questionnaires that assess participant mood and safety. Participants are asked to process the experience at home by writing a reflection about their experiences during the dosing session. This reflection is discussed at follow-up meetings.

[0171] Patients continue to wear their Apple Watch from collection of baseline measures until the end of therapy visit.Integration Periods 1-4 (Visits 6 and 7, Day 23 and 30 and Visits 9 and 10, Day 38 and 45)

[0172] After the first dosing session, participants have 2 weeks of therapy integration sessions (2 hour / week), with the first session to take place the day after the psilocybin administration session. Psychotherapy with the same two therapists occur during this period with a focus on integration, helping participants gain insight and understanding from the experience. During Visit 7, patients also prepare for the second dose of psilocybin. Similar to Visits 6 and 7, Visits 9 and 10 follow the second dose of psilocybin, with visit 9 occurring the day after the second after the second psilocybin administration.

[0173] If deemed necessary by the participant’s assigned lead therapist, additional clinical contact such as phone check ins or additional integration visits may be added. These visits can occur in person or via a video conference platform.

[0174] Selected instruments, including the IBS-SSS, VSI, and PGI-C are administered during these integration sessions (estimated time burden: less than 15 minutes.) Patients also continue to wear their Apple Watch from collection of baseline measures until the end of the second phenotyping visit. Patients will continue to respond to daily ePRO prompts regarding abdominal pain and stool frequency / consistency.End of Therapy (Visit 11, Day 52)

[0175] The EOT assessment occur approximately 15 days after the second dosing session, when participants complete their final deep phenotyping session, repeating the questionnaires from the initial phenotyping session. Regardless of whether a participant completes the integration sessions, participants are asked to complete all EOT and followup assessments if they have received at least 1 dose of psilocybin.

[0176] Patients also continue to wear their Apple Watch from collection of baseline measures until the end of therapy visit.

[0177] Patients additionally undergo an fMRI scan and EEG during this visit.Follow-up Period (Visits 12, 13, 14, Day 120, Day 240, Day 365)

[0178] Patient reported outcome measures are administered to each participant at 3-, 6-, and 12- months after the completion of baseline measures to examine persistence of changes of psilocybin and the therapy sessions. These visits can occur in person or via a video conference platform.Rationale for Study Design

[0179] This study is a pilot study designed to understand the safety and potential benefits of psilocybin in concert with psychotherapy in the chronic pain management of IBS.Participants must be 21 to 64 years of age, inclusive, at the time of signing the informed consent form.Study Population

[0180] Candidates who express an interest in participating in this study undergo electronic pre-screening. Prior to coming in for the screening visit, potential participants are asked questions to see if they meet the inclusion / exclusion criteria. If they meet these criteria and are interested in participating, potential participants provide informed consent electronically or will be invited to come in for the official screening visit, at which time obtaining informed consent will be completed.

[0181] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be permitted.Inclusion Criteria

[0182] Participants are eligible to be included in the study only if all of the following criteria apply:Age1. Participant must be 21 to 64 years of age, inclusive, at the time of signing the informed consent form.Type of Participant and Disease Characteristics2. Participant has a body mass index (BMI) between 18.5 and 29.93. Have a clinical diagnosis of irritable bowel syndrome (any subtype) as defined by the Rome IV clinical criteria:a. Abdominal pain at least 4 days per month over at least 2 months associated with one or more 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 fully explained by another medical condition Have “treatment resistant” IBS by having all of the following: a. symptoms for more than 12 months by history b. received adequate explanation and reassurance for symptoms as documented by a gastroenterologist in the medical record c. tried at least one dietary intervention by history d. tried at least one pharmacologic agent for at least six weeks by history Have attempted a gut-brain behavior therapy for at least six weeks by history Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least 2 months prior to screening and is expected to remain stable during participation in the study. Participant must be a non-smoker (tobacco) by history. Participant must be medically stable as determined by screening for medical problems via a personal interview and / or, a medical questionnaire, and an ECG, within 1 month of starting active intervention (performed during screening). Participant must agree to consume approximately the same amount of caffeine- containing beverage (e.g., coffee, tea, cola) that he / she consumes on a usual morning, before arriving at the research unit on the mornings of psilocybin session days. If the participant does not routinely consume caffeinated beverages, he / she must agree to not do so on the psilocybin session day10. Participant must agree to refrain from using any psychoactive drugs, including alcoholic beverages and nicotine, within 24 hours before and after each psilocybin administration. The exception is caffeine.11. Participant must agree to not take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours before and after each psilocybin administration.12. Participant must agree to not take any pro re nata (PRN) medications on the mornings of psilocybin sessions.13. Participant must agree that for 7 days before each psilocybin session, he / she will refrain from taking any nonprescription medication, cannabis, nutritional supplement, or herbal supplement except when approved by the Principal Investigator. Exceptions will 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.14. Participant must have at least a high school level of education or equivalent (e.g., General Educational Development [GED] Test).15. Participant must demonstrate ability to track abdominal pain and stool frequency and consistency daily in the ePRO system.16. Participant must demonstrate ability to wear Apple Watch for daily heart rate tracking.17. Participant must be willing to attempt fMRI scan and EEG.Sex and Contraceptive / Barrier Requirements18. Contraceptive use by women and men should be consistent with local regulations regarding 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 plusa barrier contraception, abstinence, vasectomized sole partner, or double barrier contraception.19. Females of reproductive potential must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline [deep phenotyping] visit until the EOT [deep phenotyping] visit).20. Sexually active male participants and / or their female partners must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline [deep phenotyping] visit until the EOT [deep phenotyping] visit) of the male participant. Male participants must also agree not to donate sperm for the duration of active intervention.Informed Consent21. Participant has provided informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (IGF) and in this protocol.

[0183] Participants will be excluded from the study on the basis of the following criteria:Medical Conditions1. Participant has had (within the past 1 year) a cardiovascular condition such as coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e. , QTc > 450 msec), artificial heart valve, or transient ischemic attack.2. Participant has epilepsy with a history of seizures.3. Participant has insulin-dependent diabetes.4. Participant is taking an oral hypoglycemic agent and has a history of hypoglycemia.5. Participant has active auto-immune disease (e.g., lupus, rheumatoid arthritis).6. Participants has any clinically significant lab abnormalities per a complete blood count and metabolic panel (e.g., elevated liver enzymes) at time of screening, and additional screening labs to exclude organic disease within the past two years.7. Participant has a current or past history of meeting Diagnostic and Statistical Manual of Mental Disorders, 5thedition (DSM-5) criteria for schizophreniaspectrum or other psychotic disorders (except substance / medication-induced or due to another medical condition), or bipolar I or II disorder measured via SCID-5 and SCID-5-PD.8. Participant has a current or past history (within 1 year) of meeting DSM-5 criteria for a moderate or severe alcohol, tobacco, or other drug use disorder (excluding caffeine) measured via relevant questions from the SCID-5.9. Participant meets Rome IV criteria for the diagnosis of centrally mediated abdominal pain syndrome (CAPS). Other co-morbid Rome IV diagnoses are not exclusion criteria.10. Participant has a history of a medically significant suicide attempt.11. Participant does not meet institutional guidelines and safety measures for MRI (e.g., has metal in the body or severe claustrophobia)Prior / Concomitant Therapy12. Participant is taking psychoactive prescription medication (e.g., opioids, tramadol, benzodiazepines) on a regular basis (i.e. , more than 2 times a week).13. Participant is currently taking an antidepressant or neuromodulator. Participants will also be required to refrain from using antidepressant medications through the completion of primary outcome assessments. Note: if a participant self-initiates a medication taper with the consent and support of their physician, they can rescreen after the appropriate time period.14. Participant is currently taking on a regular (e.g., daily) basis any medications having a primary 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 5 halflives of the agent have elapsed after the last dose.15. Subjects taking serotonin-acting dietary supplements (such as 5-hydroxy- tryptophan or St. John’s wort) due to the potential for their interaction with psilocybin and increased safety risks.16. Subjects taking prohibited medications. The list of prohibited medications includes antihypertensive medications, LIGT1A9 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).17. 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).18. Participant has any use of hallucinogens in the past 6 months or has had a total lifetime hallucinogen use of 10 or more times.19. Participant tests above 0.02% blood alcohol content on breath alcohol testing and / or positive for cocaine, methamphetamine, or opioids on urine drug testing.20. Participant has a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin.Prior / Concurrent Clinical Study Experience21. Participant is currently in another clinical trial.Diagnostic assessments22. Participant has a significant suicide risk as defined by: a. suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past year at Screening or at Baseline; or b. suicidal behaviors within the past year; or c. clinical assessment of significant suicidal risk during participant interviewsOther Exclusions23. Participant is pregnant (as indicated by a positive urine pregnancy test assessed at Screening and before the psilocybin session) or nursing.24. Participant is a WOCBP (Woman of Child Bearing Potential) and sexually active, or a man and sexually active, and not practicing an effective means of birth control.25. Participant has a confirmed first- or second-degree relative with schizophrenia spectrum or other psychotic disorders (except substance / medication-induced or due to another medical condition), or bipolar I or II disorder.26. Participant is unable to complete 10 / 14 days of ePRO tracking during run-in period.Lifestyle Considerations

[0184] Some lifestyle considerations (e.g., diet, smoking habits, alcohol, or recreational drug consumption) could be of relevance for this study. Therefore, the following restrictions apply:• Caffeine-containing beverages are allowed during the study, including on psilocybin session days. However, participants are expected to consume approximately the same amount of caffeine-containing beverages that they usually consume before arriving at the research unit on the mornings of psilocybin drug sessions.• Participants must be non-smokers (tobacco) before and during the entire study.• Psychoactive drugs, including prescription and recreational drugs, are only allowed during the study period as described in the study protocol.• For 7 days before each psilocybin session, participants must refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the Principal Investigator. Exceptions must be evaluated by the Principal Investigator and may include acetaminophen, non-steroidal antiinflammatory drugs, and common doses of vitamins and minerals. No PRN medications are allowed on the mornings of psilocybin administration.• Drugs such as sildenafil (Viagra®), tadalafil, or similar medications are not allowed within 72 hours before and after each psilocybin administration.

[0185] There are no restrictions on physical activity during the study. Session days are held under the supervision of two therapists who are present throughout the session. Sessions are conducted in a room designed to be quiet, comfortable, and aesthetically pleasing, and participants are encouraged to wear eyeshades and listen to a program of music through headphones during the drug exposure to aid them in focusing their attention inward.

[0186] Participants should agree to not drive or operate machinery on the days of psilocybin administration. Participants must agree to be driven home after psilocybin sessions. Once they are considered to be medically stable post-dose by the Investigator, participants are discharged and should accompanied for the evening by a family member or caregiver.Screen Failures

[0187] Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAE.

[0188] Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened. If a participant is taking an exclusionary medication at screening, and the participant and their health care provider(s) agree that it is appropriate to change medication(s), then rescreening may occur after the appropriate washout period.

[0189] Rescreened participants should be assigned a new participant number for every screening / rescreening event.Criteria for Temporarily Delaying Enrollment or Administration of Study Intervention

[0190] If any of the stopping rules below is met, dosing will pause until the SRC convenes (either routine or ad hoc) to review details of the event and / or additional data. If, after further review of the data, the SRC determines that no stopping rule has been met (e.g., AE determined to be unrelated to the study drug) or that if a stopping rule has been met there is a way to safely continue the trial (e.g., appropriate safety monitoring can be implemented), then dosing may resume. The occurrence of any of the following events will result in a temporary halt of dosing:• one SAE considered at least possibly related to the study drug• one Grade 3 or Grade 4 AE considered at least possibly related to the study drug• clinically similar Grade 2 AEs considered at least possibly related to the study drug in 2 participants• HPPD in a previously-dosed participant.

[0191] The study may be discontinued at any time by the Institutional Review Board (IRB), the FDA, or other government agencies as part of their duties to ensure that research participants are protected.Study Intervention(s) and Concomitant Therapy

[0192] In this protocol, study intervention is the combination of the investigational PSILOCYBIN and psychotherapy. This Section covers the administration of PSILOCYBIN; psychotherapy treatment is covered in more detail in the Psychotherapy Manual.Psilocybin Administration

[0193] Participants are instructed to consume a light, low-fat breakfast before PSILOCYBIN administration. Capsules of PSILOCYBIN are administered orally with 8 ounces of water at the research unit under the supervision of study staff. Capsules should not be opened or chewed. The drug session will be rescheduled if a friend or family member of the participant is not available to accompany them home after being discharged from the research unit.Vital Signs

[0194] Heart rate and BP are assessed before psilocybin administration and at 30, 60, 90, 120, 180, 240, 300, and 360 minutes after capsule administration. Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Blood pressure and pulse measurements are assessed with a completely automated device. Manual techniques will be used only if an automated device is not available. If a patient’s blood pressure is >200systolic or >110 diastolic for more than 15 minutes (i.e. 4 consecutive readings) they will be transferred to emergency department whether or not they are symptomatic.ECG

[0195] ECG are performed before psilocybin administration and after drug effect has abated, before leaving the research unit.Adverse Events

[0196] Adverse events will be assessed throughout the study as detailed above.

[0197] New onset of suicidal ideation is considered an AE. Suicidal ideation is assessed during every in-person visit using the C-SSRS and clinical assessment during participant interviews. The C-SSRS was developed by researchers at Columbia University and is widely used in clinical and research settings. Significant suicidal ideation is endorsed on items 4 or 5 on the C-SSRS.Efficacy Assessments (Secondary and Exploratory Endpoints)

[0198] Time points for the efficacy assessments are provided in Table 2

[0199] All efficacy assessments measured by questionnaires or surveys are collected electronically for inclusion in the electronic data capture (EDC) database. Responses are transmitted daily to a database and held until the end of the study.Patient Reported Outcomes (Secondary Efficacy Endpoints)Average Weekly Pain Score

[0200] To evaluate the efficacy of oral psilocybin to treat chronic abdominal pain in patients with IBS, the weekly average of worst daily (in past 24 hours) abdominal pain score of > 3.0 on a 0 to 10 point scale is compared in the seven days prior to collection of baseline measurements (day -7 to day 0), compared to the weekly average worst daily pain score over the seven days prior to EOT visit.

[0201] Pain is measured daily using an electronic pain diary. Participants receive a message via text or email at 6pm each evening with the PI-NRS questions. If the participant does not respond within 2 hours, a reminder text or email will be sent at 8pm. Response options will be closed at midnight. Participants who miss a day will be contacted the following day to remind them to complete their daily diary.Stool Frequency

[0202] Stool frequency is measured daily using an electronic stool diary. Participants receive a message via text or email at 6pm each evening with the stool frequency questions. If the participant does not respond within 2 hours, a reminder text or email will besent at 8pm. Response options will be closed at midnight. Participants who miss a day will be contacted the following day to remind them to complete their daily diary.

[0203] For IBS-C, stool frequency as measured by number of complete spontaneous bowel movements (CSBMs) per week are assessed. As with the average weekly pain score, the average daily CSBMs are compared for the week prior to baseline measurements vs. the week prior to EOT visit. A Stool Frequency Weekly Responder is defined as a patient who experiences an increase of at least one CSBM per week from baseline. Stool frequency is measured as an additional secondary endpoint for patients with IBS-D, but this group is analyzed separately from the IBS-C group.Stool Consistency

[0204] Stool consistency is measured daily using an electronic stool diary. Participants receive a message via text or email at 6pm each evening with the stool consistency questions. If the participant does not respond within 2 hours, a reminder text or email will be sent at 8pm. Response options will be closed at midnight. Participants who miss a day will be contacted the following day to remind them to complete their daily diary.

[0205] For IBS-D, stool consistency as measured by the Bristol Stool Form Scale will be assessed. In the A Stool Consistency Weekly Responder is defined as a patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline.Domains Relevant to Chronic Pain• Anxiety and depression (as measured by Hospital Anxiety and Depression Scale) is used to assess for comorbid mood disorders.• Severity of IBS is measured by IBS-Severity Scoring System [IBS-SSS])• Gastrointestinal symptom-specific anxiety is measured by Visceral Sensitivity Index• Patient Global Impression of Change (PGI-C). The PGI-C is a questionnaire that gauges the participant’s response to medical interventions using a 7- point Likert scale ranging from 1 to 7 with 1 being “very much improved” and 7 being “very much worse” and has been used in many pain clinical trialsQuestionnaires and Forms Used During Dosing Sessions• The Mystical Experience Questionnaire (MEQ30) has been widely used to assess the mystical experiences occasioned by psychedelics. This 30-item scale includes questions that assess mystical experiences, positive mood, transcendence of time and space, and ineffability.• The Challenging Experience Questionnaire (CEQ27) assesses challenging experiences and has been frequently used in studies with psychedelics, including psilocybin. Questions assess the difficulty, meaningfulness, spiritual significance, and change in well-being attributed to the psychedelic experience.• The Psychological Insight Questionnaire is a 7-item questionnaire that assesses insights into avoidance and maladaptive patterns; and goals and adaptive patterns.• The Monitor Rating Form is used by the therapists present during the dosing session to provide ratings at different time points, including during / within the dosing session, the day after the dosing session, and at follow-up (i.e. , monitor rating of enduring effects).Qualitative (Written) Assessment

[0206] Participants are asked to write a narrative describing their experience of the psilocybin sessions (i.e., Visits 5 and 8) before their next in-person meeting. This narrative description is discussed at the integration sessions, and will also be used in qualitative analyses to investigate common themes associated with this therapy in the context of IBS. In addition, structured interviews are performed at Visit 14 to enable framework-guided rapid analysis that gauges persistent changes in behavior, thought patterns, and emotions related to the psilocybin-assisted therapy.Study Personnel Reported Outcomes (Exploratory Endpoints)Monitor Rating Form

[0207] The Monitor Rating Form is used by the therapists present during the dosing session to provide ratings at different time points, including during / within the dosing session, and at follow-up (i.e., monitor rating of enduring effects).Heart Rate Tracking

[0208] IBS patients have measurable autonomic imbalances relative to healthy controls (e.g., diminished parasympathetic modulation during deep breathing and decreased natural logarithm of high frequency power of heart rate variability [LnHF] demonstrating lower vagal tone. There is currently no data on the effects of psilocybin on the autonomic nervous system (ANS) using heart rate variability (HRV)-based measures. We plan to measure the effects of PAT using physiological data obtained from short and long-term monitoring withwearable devices including smart watches and a new generation of wearable physiologic monitors.

[0209] Wearable biosensors provide an easy unobtrusive way to record HR passively and continuously over extended periods of time. In addition, 12-lead ECG are obtained immediately before and after the psilocybin session. Using R-peak time series, parameters of HRV as a measure of autonomic balance (sympathetic vs parasympathetic) are computed. Analysis of the changes in HRV parameters prior to, during and after psilocybin exposure is conducted.Cuff Pressure Pain

[0210] Large volume, deep muscle pressure sensitivity are assessed using an MRI- compatible rapid cuff inflator (Hokanson, Bellevue, WA). This system includes an air compressor, computerized pressure controller, and a 13.5 cm by 82.5 cm Velcro-adjusted pressure cuff. Participants first receive an ascending series of cuff pressures, starting at 20 mm Hg to 40 mm Hg and increasing in 20 mm Hg steps (10 second pressures,20 second intervals) to tolerance or a maximum of 400 mm Hg. Each pressure is rated after deflation on a 0 to 100 NRS. These pain ratings are used to interpolate a series of eight tolerable cuff pressures that are delivered in pseudo-randomized order and rated individually on pain intensity and unpleasantness. Stimulus response curves are constructed for each participant and used for analysis, along with several derived variables: cuff-PPT, cuff-Pain50, and cuff-tolerance. In addition, tonic pain induced by continuous cuff pressure is assessed (tonic-cuff). Each participant’s individually calibrated Pain40-60 pressure (i.e. , pressure that evokes a 40 to 60 / 100 pain rating) is applied for 6 to 8 minutes to one gastrocnemius muscle. Pain intensity and unpleasantness ratings are obtained every 60 seconds. This tonic cuff procedure is also performed during fMRI and EEG.Electroencephalogram

[0211] Electroencephalogram data (Table 5) is acquired during the deep phenotyping visits. Participants have EEG electrodes affixed to their scalp during the study visit. The Electrical Geodesics, Inc. (EGI) EEG system is used. The EEG electrodes and the cap to hold the electrodes are disinfected after each use. The EEG electrodes have minimal risk but may cause a slight irritation to the skin that will resolve on its own.

[0212] Prior to and during the application of cuff pressures, resting EEG is collected during which time the participant merely rests with their eyes closed for 8 minutes while EEG data are acquired, followed by 8 minutes of eyes open resting EEG. Tonic pressure pain calibrated for each participant to evoke moderate pain (P30 to P50) is then applied on the calf with continuous EEG. Pain and unpleasantness ratings are captured every 60 secondsduring cuff pressure and following stimulus presentation. Another 8 minutes of resting EEG are collected after cuff pressure, with eyes closed. The EEG assessment should take a total of approximately 60 minutes to complete.Table 5: Overview of EEG ProceduresEEG=electroencephalogramEnd of Electroencephalogram

[0213] Upon completion of the EEG assessment, the electrode cap is removed. The resting EEG is used to assess metrics of oscillation power and explosive synchronization in cortical processes that may be a diagnostic of central pain in chronic pain syndromes.EEG Data Processing

[0214] Standard preprocessing and analysis procedures are applied to each individual EEG dataset at various electrode positions for the multichannel data using Matlab R2017b or newer (Mathworks, USA). Electroencephalogram preprocessing include gradient and cardiac artifact removal, down-sampling to 125 Hz to 500 Hz, high-pass filtering at 0.25 Hz, removal of 60 Hz line noise, remove blinks and eye-movement artifacts, generation of shortterm Fourier transform spectrograms, and extraction of mean power across multiple narrow band frequencies (delta, theta, alpha, beta, gamma). Kuramoto, Stuart-Landau, and Wilson- Cohen models are used for neural mass models to simulate Explosive Synchronization and non-Explosive Synchronization brain networks for exploratory analyses.Functional Magnetic Resonance Imaging

[0215] Note: Participants who undergo MRI meet all institutional guidelines and safety measures for MRI (e.g., no metal in the body, no claustrophobia, etc.).

[0216] The MRI sessions include the following:• Structural Tl-weighted MRI• resting fMRI• proton magnetic resonance spectroscopy (1H-MRS) in the right anterior insula• proton magnetic resonance spectroscopy (1H-MRS) in the right posterior cingulate cortex (PCC)• fMRI with tonic cuff pressure evoked experimental pain• DTI to aid with spatial mapping of EEG data

[0217] Functional neuroimaging includes blood oxygenation level dependent (BOLD) fMRI at 3T using a T2*-weighted gradient echo sequence on a Siemens MR system with a 64- channel head coil. Familiarization procedures are completed prior to fMRI to reduce anxiety. Participants are instructed that the neuroimaging can be stopped at any time if a procedure becomes unbearable. The fMRI assessment should take a total of approximately 60 minutes to complete (Table 6.).Table 1: Overview of Neuroimaging Visit fMRI Procedures1H-MRS=proton magnetic resonance spectroscopy; DTI=diffusion tensor imaging; fMRI=functional magnetic resonance imagingFunctional Connectivity Magnetic Resonance Imaging

[0218] Functional connectivity MRI (fMRI) focuses on the default mode network (DMN) and salience network (SLN). The DMN is a constellation of brain regions engaged in self- referential cognition, which are “deactivated” during externally focused tasks. Patients with more centralized pain display increased connectivity between the DMN and the insula (an SLN region which is diminished with successful treatment. Whole-brain BOLD functional images are acquired on the same Siemens scanner described above, using a T2* weighted echo-planar sequence. Participants rest comfortably in the scanner with eyes closed for 8 minutes at the beginning of the scan session to obtain baseline measures of functional brain connectivity. Immediately following, participants undergo H-MRS scanning and an fMRI scan with tonic cuff pressure pain to evaluate functional brain connectivity response to deep pain. Pressure intensity are set to each participant’s Pain 30 to 50 level, as determined during the behavioral visit, and applied for 8 minutes. The pressure level from the behavioral visit are verified prior to the scan initiation and re-calibrated in the event that it evokes more or less pain than anticipated. Pain intensity and unpleasantness ratings areobtained at certain intervals during the test, up to three times and following stimulus presentation.Pre-Processing and Analyses of fMRI

[0219] Data is quality checked, pre-processed using fMRIPrep (version 1.1.8) running on the high-performance computing resources. Briefly, pre-processing steps include physiological noise removal (RETROICOR), motion correction, realignment, co-registration, normalization to standard Montreal Neurological Institute (MN I) template, regression of nuisance variables (CompCor, motion parameters), and spatial smoothing (FWHM Gaussian kernel of 6 mm). These pre-processed data is analyzed using FSL software for seed voxel connectivity and network-level dual regression ICA.1H-MRS Acquisition and Processing

[0220] 1H-MRS provides metrics amenable to longitudinal studies. High-resolution anatomical scans isolate identical brain structures within individuals over time thus minimizing error that otherwise would occur because of slight differences in voxel location from one evaluation to the next. Previous1H-MRS studies have utilized this approach to examine changes in the levels of central nervous system metabolites in test-retest studies.1H-MRS is focused on the right anterior insula cortex and the posterior cingulate cortex (PCC). The right side of the brain and these particular regions are chosen, as this these areas have been shown to be involved in chronic pain in both IBS and other chronic pain syndromes, such as fibromyalgia.1H-MRS studies are performed on the same 3T Siemens system as for fMRI. Details of the1H-MRS methods are presented in previously published work. The1H-MRS scanning protocol is PRESS with and without water suppression with multiple averages and a total scan time of approximately 5 minutes. Participants are at rest during the1H-MRS session.

[0221] The raw data undergos manual post-processing using1H-MRS software (LCModel; Stephen Provencher, Oakville, Ontario, Canada). LCModel uses a linear combination of individual spectra obtained from pure molecular species to fit the experimental spectra. Values for Glx (glutamine+glutamate) is calculated as ratios to total creatine as well as absolute concentrations using the water signal for normalization. Resulting metabolite absolute concentrations is reported in arbitrary institutional units. Since the voxels used incorporate CSF, and the volume of CSF dilutes1H-MRS-derived metabolite values, metabolite levels for CSF volume for each participant is corrected as reported previously.The1H-MRS Approach

[0222] All of the1H-MRS procedures outlined above have been successfully implemented. These studies indicate that changes in Glx and gamma aminobutyric acid (GABA) within the posterior and anterior insula are strongly correlated with improvements in pain, with reductions in clinical pain being associated with lower Glx and higher GABA levels.Similarly, the posterior cingulate cortex is known to be involved with pain processing in IBS patients.Inflammatory Markers

[0223] Bloodwork is drawn for inflammatory biomarkers (High sensitivity C-Reactive Protein, ESR, WBC, TNF-a, and IL-6) during both deep phenotyping sessions (pre- and post-PAT.) Bloodwork is drawn by research staff in the gastroenterology clinic and is sent to a central lab for processing. These biomarkers have been linked to IBS severity, particularly in IBS-D. Psilocybin demonstrates anti-inflammatory effects in vitro via activation of the 5- HT2A receptor, and there is emerging excitement about the clinical applicability of psilocybin as an anti-inflammatory agent.Other Safety AssessmentsElectrocardiograms

[0224] For screening purposes only, a single 12-lead ECG is obtained at the Screening visit using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. Participants is supine and rested for approximately 5 minutes before the ECG is recorded.

[0225] Screening ECGs are read locally by a co-investigator for determination of meeting study entry criteria.Pregnancy Testing

[0226] A urine pregnancy test was performed, and results are determined locally. Pregnancy test results must be negative at Screening, and before psilocybin is administered on the drug session day.Urine Drug and Breath Alcohol Testing

[0227] The urine drug screen is performed locally to detect tricyclic antidepressants, amphetamines, methamphetamine, MDMA (ecstasy), phencyclidine, barbiturates, benzodiazepines, cocaine, cannabis, and opioids, including opiates, oxycodone, and methadone. A breathalyzer is used to estimate the blood alcohol content.

[0228] At Screening, participants who test above 0.02% blood alcohol content and / or positive for cocaine, methamphetamine, or opioids are excluded from the study.

[0229] On drug session days, drug (excepting cannabis) and alcohol test results must be negative (blood alcohol content of less than 0.02% [verified with a second test]) before PSILOCYBIN is administered. If a participant does not have a negative result, they will be given a chance to reschedule (within the allowed window). A second failure will result in the participant’s study termination.Adverse Events, Serious Adverse Events, and Other Safety Reporting

[0230] The definitions of AEs and SAEs are set out below. Adverse event grading is performed using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.

[0231] The investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and remain responsible for following AEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study. During dosing sessions, manifestations of the psychedelic experience are be recorded as AEs unless judged by the therapists to exceed the intensity and / or duration of expected reactions.Time Period and Frequency for Collecting AE and SAE Information

[0232] All AEs and SAEs will be collected from the Baseline visit until the EOT visit, at the time points specified in Table 2. Medical occurrences that begin before Baseline deep phenotyping but after obtaining informed consent are recorded as Medical History, not as AEs.

[0233] All SAEs are recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours. The investigator will submit any updated SAE data to the sponsor within 24 hours of it being available.

[0234] Investigators are not obligated to actively seek information on AEs or SAEs after the conclusion of the study participation. However, if the investigator learns of any SAE, including a death, at any time after a participant has been discharged from the study, and he / she considers the event to be reasonably related to the study intervention or study participation, the investigator must promptly notify the sponsor.Method of Detecting AEs and SAEs

[0235] The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are provided in Recording and Follow-up of AE and / or SAE.

[0236] Care is taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and non-leading verbal questioning of the participant is the preferred method to inquire about AE occurrences.Follow-up of AEs and SAEs

[0237] After the initial AE / SAE report, the investigator is required to proactively follow each participant at subsequent visits / contacts. All SAEs are followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up.Statistical ConsiderationsAnalysis Sets

[0238] The following analysis populations have been defined for this study: Safety Population, Full Analysis Set Population (FAS), and Per Protocol (PP) Population. For this analysis, the definitions are presented in Table 7.Table 7: PopulationsAEs=adverse events; FAS=Full Analysis Set; PP=Per ProtocolGeneral Considerations

[0239] All descriptive statistical analyses are performed using SAS (Version 9.4 or higher) or R (Version 3.6.2 or higher), unless otherwise noted. For categorical variables, the number and percentage within each category of the parameter is calculated. For continuous variables, the number of participants with no missing data (n), mean, median, standard deviation (SD), minimum, and maximum values are presented.

[0240] For the purpose of statistical analyses, a month is considered equivalent to 30 days, and a year is considered equivalent to 365 days.Primary Endpoints (Safety)

[0241] The safety of treatment with PSILOCYBIN, which is evaluated by vital signs (HR and BP) and AEs, is the primary endpoint. Vital signs and AEs are collected from the Baseline (deep phenotyping) visit until the EOT visit at the time points specified in Table 2.

[0242] Descriptive statistics are used to present the count and the percentage of participants in the Safety Population who experience an AE.Secondary Endpoints (Efficacy)

[0243] The results of secondary endpoints are shown at the baseline and each follow up visits based on Full Analysis Set Population and the PP Population. Abdominal pain and stool frequency and consistency were chosen as secondary measures given their relevance to IBS symptom management and as per guidance from the FDA for IBS drug development.

[0244] The weekly average of worst daily (in past 24 hours) abdominal pain score of > 3.0 on a 0 to 10 point scale are compared in the seven days prior to collection of baseline measurements (day -7 to day 0), compared to the weekly average worst daily pain score over the seven days prior to EOT visit. Changes in the worst pain intensity from the baseline through EOT is presented in Full Analysis Set Population and the PP Population. A 30% decrease in average worst daily abdominal pain is considered a clinically significant response.

[0245] Stool frequency (which is not a primary endpoint) as measured by number of complete spontaneous bowel movements (CSBMs) per week is assessed. As with the average weekly pain score, the average daily CSBMs was compared for the week prior to baseline measurements vs. the week prior to EOT visit. A Stool Frequency Weekly Responder is defined as a patient who experiences an increase of at least one CSBM per week from baseline. Stool frequency is measured as an additional secondary endpoint for patients with IBS-D, but this group is analyzed separately from the IBS-C group.

[0246] For IBS-D, stool consistency as measured by the Bristol Stool Form Scale is assessed. A Stool Consistency Weekly Responder is defined as a patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline.

[0247] Changes from baseline to EOT in IBS symptom severity as assessed by the IBS- SSS, gastrointestinal-specific anxiety as assessed by the VSI, and comorbid anxiety and depression as measured by the HADS, and the patient’s global impression of change as measured by the PGI-C is also analyzed for the Full Analysis Set Population and the PP population.Subgroup Analysis

[0248] Given the variability of symptomatology in patients with IBS-C vs. IBS-D vs. IBS-M, these subgroups are analyzed separately for stool frequency and stool consistency changes as described above. This data is exploratory only given the small sample sizes planned in this study. For the remainder of analyses, including changes in abdominal pain, no subgroup analyses are planned.Example 2: Results

[0249] As shown in Table 8, IBS patients treated according to the above protocol with two 25 mg doses psilocybin 21 days apart demonstrated substantially improved scores in a number of metrics used to measure the severity of irritable bowel syndrome (IBS), including the IBS-Symptom Severity Score (IBS-SSS) where a score of 175-300 indicates moderately severe IBS, and a score of 300 or more indicates severe IBS. A 50 point reduction is clinically significant. Other metrics used are Visceral Sensitivity Index (VSI) which is a measure of Gl-specific anxiety, e.g. avoidance of restaurants, worry about symptoms. Patient Global Impression of Change (PGI-C) scores also improved and these reflect the patient's belief about the efficacy of the treatment. Hospital Anxiety and Depression Scores (HADS) also improved indicating that the severity of the emotional component of IBS had lessenedTable 8: Improvement in UBS metrics

[0250] In addition, as shown in Figure 2, daily pain ratings decreased after the first dose of psilocybin and remained low after the second dose, compared to the ratings before dosing.

[0251] Patients wore a smart watch for the duration of the treatment to record sleep and activity patters. There was a noticeable increase in sleep duration after the second dose compared to the duration of sleep before dosing. Activity, particularly low intensity activity, noticeably increased after each of the first and second doses.

[0252] The Pictorial Representation of Illness and Self Measure (PRISM) allows patients to visualize and evaluate the burden of suffering caused by IBS. The Self-Illness Separation (SIS) score is a measurement of the perceived relationship between a patient's sense of self and their illness. It is calculated using the Pictorial Representation of Illness and Self (PRISM) tool. Specifically, a patient places a red disk representing "illness" on a white board that represents their "life at the moment". The distance between the centre of the yellow circle representing the patient's "self" and the centre of the red disk is measured in millimetres and a shorter distance indicates a higher burden of suffering, or a stronger sense of enmeshment between the patient's self and their illness. In this case, and as shown in Figure 2, there was a significant improvement in the SIS score for patients treated with psilocybin. In this example and average SIS score of 2.3 before dosing improved to an average score of 4.59 after dosing.

[0253] 1H magnetic resonance spectroscopy (MRS) was used to assess the neurochemical state of the brain before and after dosing. Figure 3 illustrates that in the anterior insula, the amount of glutamate / glutamine (Glx) increases significantly after dosing with psilocybin. Increased Glx in the anterior insula indicates that there is enhanced glutamatergic neurotransmission. In some embodiments this facilitates classical conditioning and amenability to psychotherapy .

Claims

Claims:

1. A method of treating a disorder of gut-brain interaction (DGBI) in a subject, the method comprising: administering to the subject a therapeutically effective dose of a psychedelic compound selected from psilocin (4-hydroxy-N,N-dimethyltryptamine), psilocybin ([3-(2- dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate), 4-hydroxytryptamine, 4- hydroxy-N-methyltryptamine, [3-(aminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, [3-(2- trimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N,N,N- trimethyltryptamine, a derivative thereof, a crystalline form thereof, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein treating comprises alleviating at least one symptom of the DGBI.

3. The method of claim 2 wherein the symptom is selected from pain, abdominal discomfort, adnominal pain, cramping, bloating, excess abdominal gas, indigestion, changes in patterns of bowel movement, diarrhoea alternating with constipation, mucus in the stool, fatigue, depression, anxiety, abnormal bowel movement, stool form (appearance), frequency of bowel movements, urgency of bowel movements, or the feeling of incomplete bowel movement.

4. The method of any one of claims 1 to 3 wherein the treating comprises: reducing one or more of the IBS-Symptom Severity Score (IBS-SSS), Visceral Sensitivity Index (VSI), Patient Global Impression of Change (PGI-C) score, Hospital Anxiety and Depression Scores (HADS); reducing pain; increasing the self-illness separation score (SIS Score); increasing glutamate / glutamine (Glx) in the anterior insula of the patient.

5. The method of claim 4 wherein the IBS-Symptom Severity Score (IBS-SSS) is reduced by 50 points or more..

6. The method of any one of claims 1 to 5, wherein the psychedelic compound is psilocin or psilocybin, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, wherein the method further comprises inducing a psychedelic state in the subject by administering the compound.

8. The method of claim 7, wherein the psychedelic state has a duration of 0.5, 1, 2, 3, 4, 5, or 6 hours.

9. The method of any one of claims 1 to 8, wherein administration is subcutaneous, oral, intravenous, transdermal, intramuscular, intranasal, intranasal / pharanygeal, or buccal.

10. The method of claim 9, wherein administration is oral administration.

11. The method of claim 9, wherein administration is intravenous administration.

12. The method of any one of claims 1 to 11 , wherein the method further comprises providing psychological support to the subject during the psychedelic state.

13. The method of any one of claims 1 to 12, wherein the method further comprises providing psychological support after the patient has exited the psychedelic state.

14. The method of claim 12 or 13, wherein the psychological support is one or more of cognitive behavioural therapy, and mindfulness based therapy.

15. The method of any one of claims 1 to 14, wherein the DGBI is irritable bowel syndrome (IBS), functional dyspepsia, or reflux sensitivity.

16. The method of claim 15, wherein the IBS is diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or mixed-type IBS (IBS-M).

17. The method of claim 15 or 16, wherein the IBS is associated with an eating disorder, migraine, fibromyalgia, anxiety or depression.

18. The method of any one of claims 1 to 17, wherein the compound is administered simultaneously or sequentially with at least one additional therapeutic agent.

19. The method of claim 18, wherein at least one additional therapeutic agent is selected from a non-steroidal anti-inflammatory, prokinetic, laxative, antispasmodic, analgesic, tricyclic antidepressant, selective serotonin reuptake inhibitor, serotoninnorepinephrine reuptake inhibitor, a non-absorbable antibiotic, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, opioid receptor modulator, guanylate cyclase 2C agonist, and a chloride channel-2 agonist.

20. The method of any one of claims 1 to 19, further comprising establishing severity or symptoms in a baseline period before the administration of the psychedelic.

21. The method of claim 20, wherein the method improves one or more symptoms of IBS compared to the one or more symptoms in the baseline period.

22. The method of claim 20 or 21, wherein the symptom is selected from pain, abdominal discomfort, adnominal pain, cramping, bloating, excess abdominal gas, indigestion, changes in patterns of bowel movement, diarrhoea alternating with constipation, mucus in the stool, fatigue, depression, anxiety, abnormal bowel movement, stool form (appearance), frequency of bowel movements, urgency of bowel movements, or the feeling of incomplete bowel movement.

23. The method of claim 22, wherein the symptom is abdominal discomfort or adnominal pain.

24. The method of any one of claims 1 to 23, further comprising administering at least one further dose of the psychedelic.

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