Treatment of adjustment disorder

Abstract

The present disclosure relates to methods of treating adjustment disorder in subjects diagnosed with a disease or disorder by administering the compounds and pharmaceutical compositions described herein.

Description

Attorney Docket No.: 145737-0182 (008WO)TREATMENT OF ADJUSTMENT DISORDER1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 729,808, filed on December 9, 2024, the contents of which are incorporated herein by reference in their entirety.2. BACKGROUND

[0002] Adjustment Disorder (AjD) describes a maladaptive emotional and / or behavioral response to an identifiable psychosocial stressor in which the response occurs at a level disproportionate to the severity or intensity of the stressor, or where the symptoms cause functional impairment. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5thedition, (DSM-5) Text Revision (DSM-5-TR) defines AjD as the development of emotional or behavioral symptoms in response to an identifiable stressor(s) within 3 months of the onset of the stressor(s). Research identified that stressor events may include events such as interpersonal conflict, death of a loved one, unemployment, financial difficulties, or illness of a loved one or oneself.

[0003] Cancer or other medical illnesses such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease (PD), or idiopathic pulmonary fibrosis (IPF) can be distressing for both patients and their caregiver(s). In addition to suffering mounting physical debility, and the prospect and management of disease-related interventions, patients must deal with the emotional impact of their illness and a potentially poor prognosis; with the psychological distress further adversely affecting their quality of life. For instance, data show that patients living with cancer commonly face not only a wide range of physical symptoms but also psychological, social, and existential problems related to cancer and its treatment, during both treatment and long-term follow-up. Psychiatric comorbidities such as depression and anxiety in respiratory conditions such as IPF not only influence quality of life, but may negatively influence the clinical course of the disease and may lead to poor treatment adherence. Similar adverse effects on quality of life are also seen in patients with psychiatric disorders comorbid to ALS, MS, or PD.

[0004] Early studies have shown prevalence rates of AjD in cancer varying from 6% to over 19%, as measured using diagnostic interviews. Meta-analysis on the point prevalence of AjD among cancer patients was estimated to be 19%. In a recent large study in a population of1 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mixed cancer patients who had their cancer diagnosis for an average 13.5 months, 11% of patients had AjD (independent of other psychological disorders such as anxiety or depression) within the 4 weeks prior to the study. Prevalence rates of AjD (defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) are 14.0-34.7% in patients with advanced cancer and 10.6-16.3% in patients with terminal illness.

[0005] AjD also affects patients with other medical illnesses. For instance, approximately 22% of patients with MS have been shown to have AjD and up to 30% have been shown to have depressive symptoms. While the incidence of AjD has not been widely reported in ALS, PD, or IPF, the incidence of depressive symptoms in these populations ranges from approximately 23-49% depending on the population and instrument used to detect depressive symptoms. Specifically, 23-32% of PD patients, 24-49% of IPF patients, and 23-32% of ALS patients have depressive symptoms, with 13% of ALS patients presenting with depressive symptoms within 6 months of diagnosis).

[0006] There are currently no Food and Drug Administration (FDA)-approved pharmacotherapies or evidence-based combined pharmacological-psychosocial interventions to treat AjD. At present, psychiatric pharmacotherapies include antidepressants (e.g., citalopram), antipsychotics (e.g., olanzapine), and anxiolytics (e.g., lorazepam). Although the use of pharmacotherapy in cancer-related or other illness-related psychiatric conditions is common, meta-analysis fails to show superiority of antidepressants over placebo, and there is insufficient evidence to substantiate the effectiveness of anxiolytic treatment). Moreover, the onset of clinical improvement with many currently prescribed pharmacotherapies is delayed, relapse rates are high, and significant side effects compromise treatment adherence.

[0007] There is an unmet need for effective treatments for AjD.SUMMARY

[0008] In one aspect, the present disclosure provides a method of treating adjustment disorder (AjD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, wherein the compound is represented by:2 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)or is a pharmaceutically acceptable salt or zwitterion thereof (referred to herein as “a compound of the present disclosure”). In some embodiments, from 25 mg to 50 mg of the compound is administered to the subject. In some embodiments, from 25 mg to 35 mg of the compound is administered to the subject, e.g., 30 mg. In some embodiments, from 25 mg to 50 mg of a zwitterion of compound 1 is administered to the subject. In some embodiments, from 25 mg to 35 mg of a zwitterion of compound 1 is administered to the subject, e.g., 30 mg. In some embodiments, the compound is administered in the form of a pharmaceutical composition described herein, e.g., a liquid pharmaceutical composition. In some embodiments, a single dose of the compound is administered to the subject. In some embodiments, the subject’s adjustment disorder is associated with a primary disease or disorder, e.g., amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), idiopathic pulmonary fibrosis (IPF), and cancer. In some embodiments, treatment with a compound of the present disclosure improves one or more of the subject’s depressive symptoms and / or one or more of the subject’s anxiety symptoms.

[0009] In one aspect, the present disclosure provides a liquid pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable diluent. In some embodiments, a liquid pharmaceutical composition comprises a zwitterion of compound 1 and a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a liquid pharmaceutical composition comprises from 25 to 50 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a liquid pharmaceutical composition comprises from 25 to 50 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a liquid pharmaceutical composition comprises from 30 mg to 40 mg (e.g., 33 mg) of a zwitterion of compound 1 and a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride.3 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0010] In one aspect, the present disclosure provides a kit comprising: (a) a first composition comprising a compound of the present disclosure in solid form, and (b) a second composition comprising a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising from 30 to 40 mg of the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising from 30 mg to 40 mg (e.g., 36 mg) of the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent, e.g., a diluent comprising sodium phosphate dibasic and sodium chloride.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0012] FIG. 1 shows a schematic of the schedule of events for the clinical trial described in Example 1. “C. 1” refers to compound 1.4. DETAILED DESCRIPTION4.1. Definitions

[0013] When describing the embodiments of the present disclosure, the following terms, if present, have the following meanings, unless otherwise indicated. If not otherwise defined, terms have their customary meaning in the relevant art.

[0014] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited4 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0015] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily5 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0016] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower 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. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.

[0017] As used herein, “pharmaceutical composition” refers to a composition suitable for administration to a subject that comprises compound 1 or a salt or zwitterion thereof and one or more pharmaceutically acceptable excipients and / or diluents.

[0018] As used herein, “pharmaceutically acceptable excipient”, as used herein refers to, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for subcutaneous administration that do not deleteriously react with compound 1 or a salt or zwitterion thereof.

[0019] As used herein, “pharmaceutically effective diluent,” refers to, for example, pharmaceutically, physiologically acceptable liquids suitable for subcutaneous administration that do not deleteriously react with compound 1 or a salt or zwitterion thereof.

[0020] As used herein, “subject” refers to the person or organism to which the composition is, or is intended to be, administered. As such, subjects of the invention may include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees and other ape and monkey species. In preferred embodiments, the subject is a human. The term subject includes a person or organism of any age, weight, or other physical characteristic, including an adult, an adolescent, a child, an infant or a newborn.6 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0021] As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventive effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease or condition, and / or also lessening the severity or frequency of symptoms of the disease or condition. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple doses. For any particular therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0022] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0023] As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.4.2. Method of Treatment7 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0024] In one aspect, the present disclosure provides a method of treating adjustment disorder (AjD) in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound, wherein the compound is represented by:or is a pharmaceutically acceptable salt or zwitterion thereof.

[0025] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of compound 1. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a hydrochloride salt of compound 1. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable zwitterion of compound 1. In some embodiments, the pharmaceutically acceptable zwitterion of compound1 is represented by:

[0026] In some embodiments, AjD refers to a maladaptive emotional and / or behavioral response to an identifiable psychological stressor in which the response occurs at a level disproportionate to the severity or intensity of the stressor, or where the symptoms cause functional impairment. In some embodiments, AjD occurs within one week of the stressor. In some embodiments, AjD occurs within two weeks of the stressor. In some embodiments, AjD occurs within one month of the stressor. In some embodiments, AjD occurs with two months of the stressor. In some embodiments, AjD occurs within 3 months of the onset of the stressor. In some embodiments, AjD occurs within 6 months of the onset of the stressor.8 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0027] In some embodiments, the stressor can be the onset of symptoms of a primary disease or disorder in the subject. In some embodiments, the stressor can be diagnosis of a primary disease or disorder in the subject. In some embodiments, the subject is diagnosed with a primary disease or disorder by a medical professional.

[0028] In some embodiments, the adjustment disorder is associated with a primary disease or disorder. In some embodiments, the subject has a primary disease or disorder. In some embodiments, the subject has been diagnosed with a primary disease or disorder. In some embodiments, the primary disease or disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), idiopathic pulmonary fibrosis (IPF), and cancer. In some embodiments, the primary disease or disorder is ALS. In some embodiments, the primary disease or disorder is MS. In some embodiments, the primary disease or disorder is PD. In some embodiments, the primary disease or disorder is IPF.

[0029] In some embodiments, the primary disease or disorder is cancer. Non-limiting examples of cancer include colorectal cancer, lung cancer, melanoma, kidney cancer, endometrial cancer, brain tumors, leukemia, prostate cancer, bladder cancer, pancreatic cancer, salivary gland cancer, liver cancer, bone cancer, breast cancer, lymphoma, skin cancer, cervical cancer, sarcoma, myeloma, head and neck cancer, uterine cancer, ovarian cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Kaposi sarcoma, AIDS- related lymphoma, primary CNS lymphoma, anal cancer, basal cell carcinoma, bile duct cancer, bladder cancer, Burkitt lymphoma, non-Hodgkin lymphoma, Hodgkin’s lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, esophageal cancer, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, gallbladder cancer, stomach cancer, gastrointestinal neuroendocrine tumors, gastrointestinal stromal tumors, germ cell tumors, gestational trophoblastic disease, heart tumors, Langerhans cell histiocytosis, non-small cell lung cancer, small cell lung cancer, pleuropulmonary blastoma, pulmonary inflammatory myofibroblastic tumor, tracheobronchial tumor, skin cancer, mesothelioma, multiple endocrine neoplasia symptoms, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, neuroblastoma, gastrointestinal tumors, paraganglioma, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, primary peritoneal cancer, rectal cancer, retinoblastoma, small intestine cancer, testicular cancer, thyroid cancer, urethral cancer, vaginal cancer, vulvar cancer, and vascular tumors.9 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0030] In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject is being treated with a selective serotonin reuptake inhibitor (SSRI). In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject is not being treated with a SSRI. In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject is being treated with psychotherapy. In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject is not being treated with psychotherapy.

[0031] In some embodiments, the subject receives concomitant treatment with a SSRI when a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered, e.g., a stable regimen of a SSRI administered to the subject in regular intervals before and after treatment with a compound of the present disclosure. In some embodiments, the subject receives concomitant psychotherapy treatment when a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered, e.g., a stable regimen of a psychotherapy administered to the subject in regular intervals before and after treatment with a compound of the present disclosure. In some embodiments, the subject receives concomitant treatment with a SSRI and psychotherapy when a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered.

[0032] In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject meets DSM-5-TR diagnostic criteria for AjD. In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject meets DSM-5-TR diagnostic criteria for AjD for at least one week. In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject meets DSM-5-TR diagnostic criteria for AjD for at least two weeks. In some embodiments, prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject meets DSM-5-TR diagnostic criteria for AjD for at least three weeks. In some embodiments, prior10 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), the subject meets DSM-5-TR diagnostic criteria for AjD for at least four weeks. In some embodiments, the subject has five or more symptoms of major depressive disorder (MDD) and / or major depressive episode (MDE).

[0033] In some embodiments, the subject exhibits improvement of one or more depressive symptoms following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits decreased depressive symptoms following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the depressive symptoms comprise one or more of the following: lack of energy, lack of motivation, difficulty sleeping, oversleeping, difficulty staying awake, changes in appetite (e.g., loss of appetite, overeating), unplanned weight changes (e.g., weight gain, weight loss), headaches, cramps, difficulty concentrating, depressive mood, feeling hopeless, and suicidal ideation. In some embodiments, the subject’s depressive symptoms are improved within one day following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within 4 days following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within 7 days following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within two weeks following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within four weeks following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within 42 days following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within six weeks following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within two11 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) months following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within three months following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within four months following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s depressive symptoms are improved within five months following treatment. In some embodiments, the subject’s depressive symptoms are improved within six months following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0034] In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s total Montgomery -Asberg Depression Rating Scale (MADRS) score compared to a baseline total MADRS score measured prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the total MADRS is used to determine depression severity in a subject. In some embodiments, the subject’s total MADRS score is determined by a 10-item questionnaire and is administered using a modified structured interview guide for total MADRS. In some embodiments, the questionnaire is administered by a rater. In some embodiments, the rater is a medical professional. In some embodiments, improvement of one or more depressive symptoms in a subject is determined by a decrease in the subject’s total MADRS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline total MADRS score measured prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s total MADRS score compared to the baseline total MADRS score. In some embodiments, administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s total MADRS score by 0%-500% compared to the baseline total MADRS score. In some embodiments, administration of a compound of the present disclosure (i.e., compound 1 or a12 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s total MADRS score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline total MADRS score. In some embodiments, the subject exhibits at least a 20% decrease in total MADRS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline total MADRS score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% decrease in total MADRS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline total MADRS score. In some embodiments, the subject’s total MADRS score is determined by a medical professional. In some embodiments, the baseline total MADRS score is measured one day prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured two months after treatment with13 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s total MADRS score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0035] In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) improves anxiety symptoms in the subject. In some embodiments, the subject exhibits improvement of one or more anxiety symptoms following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits decreased anxiety symptoms following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms comprise one or more of the following: restlessness, irritability, difficulty concentrating, feeling fear, rapid heartbeat, sweating, trembling, nausea, dizziness, difficulty sleeping, feeling tired, and shortness of breath. In some embodiments, anxiety symptoms are improved within one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within 4 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within 7 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety14 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) symptoms are improved within six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the anxiety symptoms are improved within six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0036] In some embodiments, improvement of one or more anxiety symptoms is determined by a decrease in the subject’s Hamilton Rating Score for Anxiety (HAM- A) score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline HAM-A score measured prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the HAM-A is used to determine the severity of anxiety symptoms in a subject. In some embodiments, the subject’s HAM-A score is determined by a 14-item scale and is administered with a modified structured interview guide for the HAM-A scale. In some embodiments, the 14-item scale is administered by a rater. In some embodiments, the rater is a medical professional. In some embodiments, administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s Hamilton Rating Score for Anxiety (HAM-A) score compared to a baseline HAM-A score measured prior to administration. In some embodiments, administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s HAM-A score compared to the baseline HAM-A score measured prior to administration. In some embodiments, administration of a compound of the present15 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s HAM-A score by 0%-500% compared to the baseline HAM-A score measured prior to administration. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s HAM-A score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%< 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400$, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline HAM-A score. In some embodiments, the subject exhibits at least a 20% decrease in HAM-A score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline HAM-A score measured prior to treatment. In some embodiments, the subject’s HAM-A score is determined by a medical professional. In some embodiments, the baseline HAM-A score is measured one day prior to administration of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured two months after treatment with a compound of the present16 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM- A score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HAM-A score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0037] In some embodiments, the subject exhibits a change in Hospital Anxiety and Depression Scale (HADS) score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline HADS score measured prior to treatment. The HADS determines severity of depression and anxiety in subjects with comorbid medical conditions. In some embodiments, the subject’s HADS score is determined by a 14-item questionnaire. In some embodiments, the questionnaire is a self-report scale by the subject. In some embodiments, improvement of one or more depressive symptoms or anxiety symptoms is determined by a decrease in the subject’s HADS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline HADS score measured prior to treatment. In some embodiments, subject’s HADS score decreases following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline HADS score prior to treatment. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s HADS score by 0%-500% compared to the baseline HADS score. In some embodiments, the subject’s HADS score decreases by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline HADS score. In some17 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) embodiments, the subject exhibits at least a 20% decrease in HADS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline HADS score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% decrease in HADS score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline HADS score. In some embodiments, the subject’s HADS score is determined by a medical professional. In some embodiments, the baseline HADS score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s HADS score is measured five months after treatment with a compound of the present18 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’ HADS score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0038] In some embodiments, the subject exhibits a change in Patient Health Questionnaire-9 (PHQ-9) score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PHQ-9 score measured prior to treatment. The PHQ-9 screens for depression in subjects and also diagnoses and monitors the severity of the depression. In some embodiments, the subject’s PHQ-9 score is determined by 9 questions and asks subjects how often they have been bothered by any of the following problems in the past 2 weeks. In some embodiments, improvement of one or more depressive symptoms is determined by a decrease in the subject’s PHQ-9 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PHQ-9 score measured prior to treatment. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s PHQ-9 score compared to the baseline HADS score. In some embodiments, the subject’s PHQ-9 score is decreased by 0%-500% following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline PHQ-9 score prior to treatment. In some embodiments, the subject’s PHQ-9 score is decreased by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline PHQ-9 score. In some embodiments, the subject exhibits at least a 20% decrease in PHQ-9 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline PHQ-9 score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% decrease in PHQ-9 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline PHQ-9 score. In some embodiments, the subject’s PHQ-9 score is determined by a medical professional. In some19 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) embodiments, the baseline PHQ-9 score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PHQ-9 score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’ PHQ-9 score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0039] In some embodiments, improvement of one or more anxiety symptoms is determined by a decrease in the subject’s General Anxiety Disorder-7 (GAD-7) total score following20 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline GAD-7 score measured prior to treatment. In some embodiments, the subject exhibits a change in GAD-7 total score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline GAD-7 total score measured prior to treatment. In some embodiments, the GAD-7 is used to screen, diagnose, and assess the severity of anxiety disorder in a subject. In some embodiments, the subject’s GAD-7 total score is determined by a 7 item self-report scale by the subject. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s GAD-7 total score compared to a baseline GAD-7 total score measured prior to treatment. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s GAD-7 total score compared to the baseline GAD-7 total score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s GAD-7 total score by 0%-500% compared to the baseline GAD-7 total score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s GAD-7 total score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%< 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400$, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline GAD-7 total score. In some embodiments, the subject exhibits at least a 20% decrease in GAD-7 total score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline GAD-7 total score measured prior to treatment. In some embodiments, the subject’s GAD-7 total score is determined by a medical professional. In some embodiments, the baseline GAD-7 total score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured four days after treatment with a compound of the21 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s GAD-7 total score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0040] In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s Adjustment Disorder New Module 20 (ADNM-20) score compared to a baseline ADNM-20 score measured prior to treatment. In some embodiments, the subject exhibits a change in ADNM-20 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline ADNM-20 score measured prior to treatment. The ADNM-20 measures emotional or behavioral reactions to an identifiable stressor (e.g., acute or chronic life events) of the past 222 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) years. In some embodiments, the subject’s ADNM-20 score is determined by 6 subscales (e.g., preoccupation, failure to adapt, avoidance, depressive mood, anxiety, and impulse disturbance) and a subject indicates on a 4-point scale how often they have experienced different symptoms during the past 2 weeks. In some embodiments, the ADNM-20 is a selfreport measure by the subject. In some embodiments, improvement of one or more depressive symptoms or anxiety symptoms is determined by a decrease in the subject’s ADNM-20 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline ADNM-20 score measured prior to treatment. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s ADNM-20 score compared to the baseline ADNM-20 score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s ADNM-20 score by 0%-500% compared to the baseline ADNM-20 score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s ADNM-20 score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline ADNM-20 score. In some embodiments, the subject exhibits at least a 20% decrease in ADNM-20 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline ADNM-20 score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% decrease in ADNM-20 score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline ADNM-20 score. In some embodiments, the subject’s ADNM-20 score is determined by a medical professional. In some embodiments, the baseline ADNM-20 score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured four23 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s ADNM-20 score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’ ADNM-20 score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0041] In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s Demoralization Scale Version II (DS-II) score compared to a baseline DS-II score measured prior to treatment. In some embodiments, the subject exhibits a change in DS-II score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline DS-II score measured prior to treatment. The DS-II measures demoralization of subjects. In some embodiments, the subject’s DS-II score is determined by 2 subscales (e.g., meaning and24 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) purpose, and distress and coping ability). In some embodiments, improvement of demoralization is determined by a change in the subject’s DS-II score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline DS-II score measured prior to treatment. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s DS-II score compared to the baseline DS-II score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s DS-II score by 0%-500% compared to the baseline DS-II score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) decreases the subject’s DS-II score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, or 500% compared to the baseline DS-II score. In some embodiments, the subject exhibits at least a 20% decrease in DS-II score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline DS-II score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% decrease in DS-II score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline DS-II score. In some embodiments, the subject’s DS-II score is determined by a medical professional. In some embodiments, the baseline DS-II score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured two weeks after treatment with a compound of the present disclosure25 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)(i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s DS-II score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0042] In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) changes the subject’s Patient-Reported Outcomes Measurement Information System - Short Form (PROMIS-SF) score compared to a baseline PROMIS-SF score measured prior to treatment. In some embodiments, the subject exhibits a change in PROMIS-SF score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PROMIS-SF score measured prior to treatment. The PROMIS-SF evaluates and monitors physical, mental, and social health of a subject. In some embodiments, the PROMIS-SF comprises a questionnaire of more than 100 health- related quality of life items and includes the following subsections: Physical Function, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. In some embodiments, improvement of quality of life of the subject’s is determined by a change in the subject’s PROMIS-SF score following treatment with a26 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PROMIS-SF score measured prior to treatment. In some embodiments, the treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) increases the subject’s PROMIS-SF score compared to the baseline PROMIS-SF score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) increases the subject’s PROMIS-SF score by 0%-500% compared to the baseline PROMIS-SF score. In some embodiments, treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) increases the subject’s PROMIS-SF score by at least 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%,230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%,360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%,490%, or 500% compared to the baseline PROMIS-SF score. In some embodiments, the subject exhibits at least a 20% increase in PROMIS-SF score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline PROMIS-SF score measured prior to treatment. In some embodiments, the subject exhibits at least a 50% increase in PROMIS-SF score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to the baseline PROMIS-SF score. In some embodiments, the subject’s PROMIS-SF score is determined by a medical professional. In some embodiments, the baseline PROMIS-SF score is measured one day prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured one day after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured four days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured seven days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured two weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or27 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured four weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured 42 days after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured six weeks after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured two months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured three months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured four months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured five months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject’s PROMIS-SF score is measured six months after treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0043] In some embodiments, the subject exhibits an improvement of demoralization, general health status, pain, quality of life, or a combination thereof following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits an improvement of demoralization following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits an improvement of general health status following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits an improvement of pain following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the subject exhibits an improvement in quality of life following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt28 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) or zwitterion thereof).

[0044] In some embodiments, the subject’s improvement is determined by a change in one or more of the following: (a) demoralization scale version (II) following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline DS-II measured prior to treatment; (b) patient- reported outcomes measurement information system (PROMIS) short form (SF) v2.0- Physical Function 4a score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PROMIS-SF v2.0 Physical Function 4a score measured prior to treatment; (c) PROMIS-SF vl.O-Sleep Disturbance 4a score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PROMIS-SF vl.O-Sleep Disturbance 4a score measured prior to treatment; (d) PROMIS-SF 2.0-Fatigue 4a score following treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) compared to a baseline PROMIS-SF 2.0-Fatigue 4a score measured prior to treatment; (e) PROMIS-SF v2.0-Ability to Participate in Social Roles and Activities 4a score compared to a baseline PROMIS-SF v2.0-Ability to Participate in Social Roles and Activities 4a score measured prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof); and (f) PROMIS-SF vl.O-Pain Interference 4a score compared to a baseline PROMIS-SF vl.O-Pain Interference 4a score measured prior to treatment with a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0045] In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is a dose of 0.1 milligrams (mg) to 100 mg. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof)is a dose of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 5929 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg 1. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is a dose from 1 mg to 50 mg. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is a dose of 1.5 mg. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is a dose of 30 mg of compound 1.

[0046] In some embodiments, a dose comprising from 0.1 mg to 100 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the subject. In some embodiments, a dose comprising from 0.1 mg to 0.5 mg, 0.1 mg to 1 mg, 0.1 mg to 5 mg, 0.1 mg to 10 mg, 0.1 mg to 20 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 40 mg, 0.1 mg to 50 mg, 0.1 mg to 60 mg, 0.1 mg to 70 mg, 0.1 mg to 75 mg, 0.1 mg to 80 mg, 0.1 mg to 90 mg, 0.5 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 10 mg, 0.5 mg to 20 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 40 mg, 0.5 mg to 50 mg, 0.5 mg to 60 mg, 0.5 mg to 70 mg, 0.5 mg to 75 mg, 0.5 mg to 80 mg, 0.5 mg to 90 mg, 0.5 mg to 100 mg, 1 mg to 5 mg, 1 mg to 10 mg, 1 mg to 20 mg, 1 mg to 25 mg, 1 mg to 30 mg, 1 mg to 40 mg, 1 mg to 50 mg, 1 mg to 60 mg, 1 mg to 70 mg, 1 mg to 75 mg, 1 mg to 80 mg, 1 mg to 90 mg, 1 mg to 100 mg, 5 mg to 10 mg, 5 mg to 20 mg, 5 mg to 25 mg, 5 mg to 30 mg, 5 mg to 40 mg, 5 mg to 50 mg, 5 mg to 60 mg, 5 mg to 70 mg, 5 mg to 75 mg, 5 mg to 80 mg, 5 mg to 90 mg, 5 mg to 100 mg, 10 mg to 20 mg, 10 mg to 25 mg, 10 mg to 30 mg, 10 mg to 40 mg, 10 mg to 50 mg, 10 mg to 60 mg, 10 mg to 70 mg, 10 mg to 75 mg, 10 mg to 80 mg, 10 mg to 90 mg, 10 mg to 100 mg, 20 mg to 25 mg, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, 20 mg to 80 mg, 20 mg to 90 mg, 20 mg to 100 mg, 25 mg to 30 mg, 25 mg to 40 mg, 25 mg to 50 mg, 25 mg to 60 mg, 25 mg to 70 mg, 25 mg to 75 mg, 25 mg to 80 mg, 25 mg to 90 mg, 25 mg to 100 mg, 30 mg to 40 mg, 30 mg to 50 mg, 30 mg to 60 mg, 30 mg to 70 mg, 30 mg to 80 mg, 30 mg to 90 mg, 30 mg to 100 mg, 40 mg to 50 mg, 40 mg to 60 mg, 40 mg to 70 mg, 40 mg to 80 mg, 40 mg to 90 mg, 40 mg to 100 mg, 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 60 mg to 70 mg, 60 mg to 80 mg, 60 mg to 90 mg, 60 mg to 100 mg, 7030 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mg to 80 mg, 70 mg to 90 mg, 80 mg to 90 mg, 80 mg to 100 mg, or 90 mg to 100 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the patient. In some embodiments, a dose comprising from 25 mg to 75 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the subject. In some embodiments, a dose comprising 30 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the subject. In some embodiments, a dose comprising 1.5 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the subject.

[0047] In some embodiments, a dose comprising from 0.1 mg to 100 mg compound 1 is administered to the subject. In some embodiments, a dose comprising from 0.1 mg to 0.5 mg, 0.1 mg to 1 mg, 0.1 mg to 5 mg, 0.1 mg to 10 mg, 0.1 mg to 20 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 40 mg, 0.1 mg to 50 mg, 0.1 mg to 60 mg, 0.1 mg to 70 mg, 0.1 mg to 75 mg, 0.1 mg to 80 mg, 0.1 mg to 90 mg, 0.5 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 10 mg, 0.5 mg to 20 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 40 mg, 0.5 mg to 50 mg, 0.5 mg to 60 mg, 0.5 mg to 70 mg, 0.5 mg to 75 mg, 0.5 mg to 80 mg, 0.5 mg to 90 mg, 0.5 mg to 100 mg, 1 mg to 5 mg, 1 mg to 10 mg, 1 mg to 20 mg, 1 mg to 25 mg, 1 mg to 30 mg, 1 mg to 40 mg, 1 mg to 50 mg, 1 mg to 60 mg, 1 mg to 70 mg, 1 mg to 75 mg, 1 mg to 80 mg, 1 mg to 90 mg, 1 mg to 100 mg, 5 mg to 10 mg, 5 mg to 20 mg, 5 mg to 25 mg, 5 mg to 30 mg, 5 mg to 40 mg, 5 mg to 50 mg, 5 mg to 60 mg, 5 mg to 70 mg, 5 mg to 75 mg, 5 mg to 80 mg, 5 mg to 90 mg, 5 mg to 100 mg, 10 mg to 20 mg, 10 mg to 25 mg, 10 mg to 30 mg, 10 mg to 40 mg, 10 mg to 50 mg, 10 mg to 60 mg, 10 mg to 70 mg, 10 mg to 75 mg, 10 mg to 80 mg, 10 mg to 90 mg, 10 mg to 100 mg, 20 mg to 25 mg, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, 20 mg to 80 mg, 20 mg to 90 mg, 20 mg to 100 mg, 25 mg to 30 mg, 25 mg to 40 mg, 25 mg to 50 mg, 25 mg to 60 mg, 25 mg to 70 mg, 25 mg to 75 mg, 25 mg to 80 mg, 25 mg to 90 mg, 25 mg to 100 mg, 30 mg to 40 mg, 30 mg to 50 mg, 30 mg to 60 mg, 30 mg to 70 mg, 30 mg to 80 mg, 30 mg to 90 mg, 30 mg to 100 mg, 40 mg to 50 mg, 40 mg to 60 mg, 40 mg to 70 mg, 40 mg to 80 mg, 40 mg to 90 mg, 40 mg to 100 mg, 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 60 mg to 70 mg, 60 mg to 80 mg, 60 mg to 90 mg, 60 mg to 100 mg, 70 mg to 80 mg, 70 mg to 90 mg, 80 mg to 90 mg, 80 mg to 100 mg, or 90 mg to 100 mg compound 1 is administered to the patient. In some embodiments, a dose comprising from 25 mg to 75 mg31 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) compound 1 is administered to the subject. In some embodiments, a dose comprising from 25 mg to 35 mg, e.g., 30 mg compound 1 is administered to the subject. In some embodiments, a dose comprising 1.5 mg compound 1 is administered to the subject.

[0048] In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered via injection. In some embodiments, the injection is intravenous, intramuscular, subcutaneous, or intradermal. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered via subcutaneous (SC) injection. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered via intramuscular injection. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered via intradermal injection.

[0049] In some embodiments, a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered to the subject in the form of a liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition is a solution.

[0050] In some embodiments, a liquid pharmaceutical composition comprises from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg. In some embodiments, the liquid pharmaceutical composition comprises from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, from 30 mg to 35 mg, or from 30 mg to 40 mg. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1.32 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0051] In some embodiments, a liquid pharmaceutical composition comprises from 0.1 mg to100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from10 mg to 20 mg, or from 0.1 mg to 10 mg. In some embodiments, the liquid pharmaceutical composition comprises from 25 mg to 50 mg of the zwitterion:from 25 mg to 35 mg, from 30 to 35 mg, or from 30 mg to 40 mg. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of the zwitterion

[0052] In some embodiments, the liquid pharmaceutical composition comprises a pharmaceutically acceptable diluent. In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination thereof.

[0053] In some embodiments, the pharmaceutically acceptable diluent comprises sodium phosphate dibasic. In some embodiments, the sodium phosphate dibasic is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium phosphate dibasic is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium phosphate dibasic is 60 mM.33 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0054] In some embodiments, the pharmaceutically acceptable diluent comprises sodium chloride. In some embodiments, the sodium chloride is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium chloride is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium chloride is 40 mM.

[0055] In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

[0056] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride.

[0057] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1 and a34 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

[0058] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of the zwitterion:from 25 mg to 35 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 30 mg of the zwitterionpharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 33 mg of the zwitterion35 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride.

[0059] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of the zwitterion:from 25 mg to 35 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 30 mg of the zwitterionpharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 4036 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 33 mg of the zwitterionpharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

[0060]

[0061] In some embodiments, the liquid pharmaceutical composition comprises a single fixed dose.

[0062] In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered once a week. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered every two weeks. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered once a month. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered every two months. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered every three months. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered every four months. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered every six months. In some embodiments, the therapeutically effective amount of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) is administered once a year.37 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)4.3. Pharmaceutical Compositions

[0063] In one aspect, the present disclosure provides a liquid pharmaceutical composition comprising a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) and a pharmaceutically acceptable diluent. In some embodiments, a liquid pharmaceutical composition comprises compound 1 and a pharmaceutically acceptable diluent. In some embodiments, a liquid pharmaceutical composition comprises a pharmaceutically acceptable salt of compound 1 and a pharmaceutically acceptable diluent. In some embodiments, a liquid pharmaceutical composition comprises a hydrochloride salt of compound 1 and a pharmaceutically acceptable diluent. In some embodiments, a liquid pharmaceutical composition comprises a pharmaceutically acceptable zwitterion of compound 1 and a pharmaceutically acceptable diluent.

[0064] In some embodiments, the liquid pharmaceutical composition comprises from 0.1 milligrams (mg) to 100 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises from 1 mg to 50 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or38 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises 36 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the liquid pharmaceutical composition comprises 1.5 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0065] In some embodiments, the liquid pharmaceutical composition comprises from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg. In some embodiments, the liquid pharmaceutical composition comprises from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 30 mg to 40 mg, from 25 mg to 35 mg or from 30 mg to 35 mg. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1. In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a zwitterion of compound 1.

[0066] In some embodiments, the liquid pharmaceutical composition comprises from 0.1 mg to 100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg. In some embodiments, the liquid pharmaceutical composition comprises from 25 mg to 50 mg of the zwitterion:from 30 mg to 40 mg, from 25 mg to 35 mg, or from 30 mg to 35 mg. In some embodiments, the liquid pharmaceutical composition39 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) comprises 30 mg of the zwitterionsome embodiments, the liquid pharmaceutical composition comprises 33 mg of the zwitterion

[0067] In certain embodiments, the liquid pharmaceutical composition is in the form of a solution, such as an aqueous solution.

[0068] In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination.

[0069] In some embodiments, the pharmaceutically acceptable diluent comprises sodium phosphate dibasic. In some embodiments, the sodium phosphate dibasic is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium phosphate dibasic is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium phosphate dibasic is 60 mM.

[0070] In some embodiments, the pharmaceutically acceptable diluent comprises sodium chloride. In some embodiments, the sodium chloride is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium chloride is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium chloride is 40 mM.

[0071] In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

[0072] In certain embodiments, the liquid pharmaceutical composition has a total volume of 0.01 milliliters (mL) to 5 mL. In some embodiments, the liquid pharmaceutical composition has a total volume of O.OlmL, 0.02 mL, 0.03 mL, 0.04 mL, 0.05 mL, 0.06 mL, 0.07 mL, 0.08 mL, 0.09 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.040 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, 3.0 mL, 3.1 mL, 3.2, mL, 3.3 mL, 3.4 mL, 3.5 mL, 3.6 mL, 3.7 mL, 3.8mL, 3.9 mL, 4.0 mL, 4.1 mL, 4.2 mL, 4.3 mL, 4.4 mL, 4.5 mL, 4.6 mL, 4.7 mL, 4.8 mL, 4.9 mL, or 5.0 mL. In some embodiments, the liquid pharmaceutical composition has a total volume of 0.05 mL. In some embodiments, the liquid pharmaceutical composition has a total volume of 1.0 mL.

[0073] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride.

[0074] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of a zwitterion of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 30 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 4041 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 33 mg of a zwitterion of compound 1 and a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride

[0075] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of the zwitterion:from 25 mg to 35 mg and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 30 mg of the zwitterionpharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 33 mg of the zwitterion42 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride.

[0076] In some embodiments, a liquid pharmaceutical composition comprises (a) from 0.1 mg to 100 mg of the zwitterionfrom 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of the zwitterion:from 25 mg to 35 mg and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 30 mg of the zwitterionpharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 4043 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mM sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises (a) 30 mg of the zwitterionpharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

[0077] In some embodiments, the liquid pharmaceutical composition comprises a single fixed dose.4.4. Kits

[0078] In one aspect, the present disclosure provides a kit comprising: (a) a first composition comprising a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof) in solid form, and (b) a second composition comprising a pharmaceutically acceptable diluent.

[0079] In some embodiments, a kit comprises: (a) a first composition comprising a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent. In some embodiments, a kit comprises: (a) a first composition comprising a hydrochloride salt of compound 1 in solid form, and (b) a second composition comprising a pharmaceutically acceptable diluent. In some embodiments, a kit comprises: (a) a first composition comprising a lyophilized, pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent. In some embodiments, a kit comprises: (a) a first composition comprising a lyophilized, hydrochloride salt of compound 1 in solid form, and (b) a second composition comprising a pharmaceutically acceptable diluent.

[0080] In some embodiments, the first composition comprises from 0.1 mg to 100 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the first composition comprises 0.1 mg to 0.5 mg, 0.1 mg to 1 mg, 0.1 mg to 5 mg, 0.1 mg to 10 mg, 0.1 mg to 20 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 40 mg, 0.1 mg to 50 mg, 0.1 mg to 60 mg, 0.1 mg to 70 mg, 0.1 mg to 75 mg, 0.1 mg to 80 mg, 0.1 mg to 90 mg, 0.5 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 10 mg, 0.5 mg to 20 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 40 mg, 0.5 mg to 50 mg, 0.5 mg44 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) to 60 mg, 0.5 mg to 70 mg, 0.5 mg to 75 mg, 0.5 mg to 80 mg, 0.5 mg to 90 mg, 0.5 mg to 100 mg, 1 mg to 5 mg, 1 mg to 10 mg, 1 mg to 20 mg, 1 mg to 25 mg, 1 mg to 30 mg, 1 mg to 40 mg, 1 mg to 50 mg, 1 mg to 60 mg, 1 mg to 70 mg, 1 mg to 75 mg, 1 mg to 80 mg, 1 mg to 90 mg, 1 mg to 100 mg, 5 mg to 10 mg, 5 mg to 20 mg, 5 mg to 25 mg, 5 mg to 30 mg, 5 mg to 40 mg, 5 mg to 50 mg, 5 mg to 60 mg, 5 mg to 70 mg, 5 mg to 75 mg, 5 mg to 80 mg, 5 mg to 90 mg, 5 mg to 100 mg, 10 mg to 20 mg, 10 mg to 25 mg, 10 mg to 30 mg, 10 mg to 40 mg, 10 mg to 50 mg, 10 mg to 60 mg, 10 mg to 70 mg, 10 mg to 75 mg, 10 mg to 80 mg, 10 mg to 90 mg, 10 mg to 100 mg, 20 mg to 25 mg, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, 20 mg to 80 mg, 20 mg to 90 mg, 20 mg to 100 mg, 25 mg to 30 mg, 25 mg to 40 mg, 25 mg to 50 mg, 25 mg to 60 mg, 25 mg to 70 mg, 25 mg to 75 mg, 25 mg to 80 mg, 25 mg to 90 mg, 25 mg to 100 mg, 30 mg to 40 mg, 30 mg to 50 mg, 30 mg to 60 mg, 30 mg to 70 mg, 30 mg to 80 mg, 30 mg to 90 mg, 30 mg to 100 mg, 40 mg to 50 mg, 40 mg to 60 mg, 40 mg to 70 mg, 40 mg to 80 mg, 40 mg to 90 mg, 40 mg to 100 mg, 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 60 mg to 70 mg, 60 mg to 80 mg, 60 mg to 90 mg, 60 mg to 100 mg, 70 mg to 80 mg, 70 mg to 90 mg, 80 mg to 90 mg, 80 mg to 100 mg, or 90 mg to 100 mg a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the first composition comprises from 25 mg to 75 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof), e.g., from 30 mg to 40 mg. In some embodiments, the first composition comprises 30 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the first composition comprises 33 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the first composition comprises 36 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof). In some embodiments, the first composition comprises 1.5 mg of a compound of the present disclosure (i.e., compound 1 or a pharmaceutically acceptable salt or zwitterion thereof).

[0081] In some embodiments, the first composition comprises from 0.1 mg to 100 mg of a pharmaceutically acceptable salt of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 2045 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) mg, or from 0.1 mg to 10 mg. In some embodiments, the first composition comprises from 30 mg to 40 mg of a pharmaceutically acceptable salt of compound 1, e.g., from 30 mg to 35 mg (such as 33 mg) or from 35 mg to 40 mg (such as 36 mg).

[0082] In some embodiments, the first composition comprises from 0.1 mg to 100 mg of the HC1 salt of compound 1, e.g., from 0.1 mg to 50 mg, from 10 mg to 50 mg, from 20 mg to 50 mg, from 30 mg to 50 mg, from 40 mg to 50 mg, from 0.1 to 40 mg, from 10 mg to 40 mg, from 20 mg to 40 mg, from 30 mg to 40 mg, from 0.1 mg to 30 mg, from 10 mg to 30 mg, from 20 mg to 30 mg, from 0.1 mg to 20 mg, from 10 mg to 20 mg, or from 0.1 mg to 10 mg. In some embodiments, the first composition comprises from 30 mg to 40 mg of the HC1 salt of compound 1, e.g., from 30 mg to 35 mg (such as 33 mg) or from 35 mg to 40 mg (such as 36 mg).

[0083] In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination thereof.

[0084] In some embodiments, the pharmaceutically acceptable diluent comprises sodium phosphate dibasic. In some embodiments, the sodium phosphate dibasic is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium phosphate dibasic is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium phosphate dibasic is 60 mM.

[0085] In some embodiments, the pharmaceutically acceptable diluent comprises sodium chloride. In some embodiments, the sodium chloride is from 1 millimolar (mM) to 100 mM. In some embodiments, the sodium chloride is 1 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In some embodiments, the sodium chloride is 40 mM.

[0086] In some embodiments, the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

[0087] In some embodiments, a kit comprises: (a) a first composition comprising a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.46 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0088] In some embodiments, a kit comprises: (a) a first composition comprising 30 mg to 50 mg of a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising 30 mg to 50 mg of a pharmaceutically acceptable salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

[0089] In some embodiments, a kit comprises: (a) a first composition comprising the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

[0090] In some embodiments, a kit comprises: (a) a first composition comprising 30 mg to 50 mg of the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride. In some embodiments, a kit comprises: (a) a first composition comprising 30 mg to 50 mg of the HC1 salt of compound 1 in solid form and (b) a second composition comprising a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.5. EXAMPLESThe following abbreviations used in the examples have the definitions set forth below:47 Of 1044925-5827-3149.1Atorney Docket No.: 145737-0182 (008WO)48 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1. Example 1: Human Clinical Trial for Adjustment Disorder That Is Associated with Diseases and Disorders5.1.1. Introduction

[0071] This clinical study is designed to investigate whether a single dose of compound 1 will provide durable benefit for participants with multidimensional psychiatric distress associated with AjD due to cancer or other medical illnesses including ALS, MS, PD and IPF.5.1.2. Objective(s)

[0072] Primary study objective: Evaluate the effect of 30 mg compound 1 on depressive symptoms in patients with AjD compared to 1.5 mg. In this example, 30 mg of compound 1 was calculated as the amount of the free base of compound 1 (molecular = 374.48), which is equivalent to 33 mg of the HC1 salt of compound 1 (molecular weight = 410.94).

[0073] The primary endpoint is the change from baseline at Day 7 in MADRS total score. In the assessment of the primary endpoint, a treatment policy strategy will be used (i.e., data will be analyzed regardless of any intercurrent event post-randomization).49 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0074] Secondary study objective: (1) Evaluate the effect of 30 mg compound 1 on anxiety symptoms in patients with AjD compared to 1.5 mg compound 1 and (2) evaluate safety of compound 1.

[0075] Other study objectives:• Further Evaluate the safety of compound 1.• Evaluate the effect of 30 mg compound 1 on patient-ruled improvement and severity of symptomatology.• Further evaluate the effect of 30 mg compound 1 on clinician-rated improvement and severity of symptomatology.• Further evaluate the effect on 30 mg compound 1 on depressive and anxiety symptoms compared to 1.5 mg compound 1.• Evaluate the effect of 30 mg compound 1 on AjD symptoms compared to 1.5 mg compound 1.• Evaluate the quantitative psychoactive experience / response to compound 1.• Evaluate if 30 mg compound 1 improves demoralization, general health status, pain, and / or quality of life compared to 1.5 mg compound 1.

[0076] For further details regarding the study objectives, please see Table 1.Table 1. Clinical Trial Objectives and Endpoints50 Of 1044925-5827-3149.1Atorney Docket No.: 145737-0182 (008WO)51 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1.3. Study Overview

[0077] This study is a Phase 2, randomized, double-blind, parallel-group, dose-controlled study evaluating the safety and efficacy of a single dose of compound 1 (30 mg or 1.5 mg) administered as a SC injection for the treatment of AjD with depressed mood, or mixed anxiety and depressed mood in patients with cancer or other illnesses including ALS, MS, PD, or IPF. Diagnosis will be based on DSM-5-TR criteria using a Structured Clinical Interview for DSM-5-TR Axis I Disorders Clinical Trial Version (SCID-5-CT).

[0078] Approximately 100 participants (50 per dose group) will be randomized 1 : 1 to receive 30 mg compound 1 or 1.5 mg compound 1, administered as a single SC injection in a clinic setting. Randomization will be constrained such that 80 participants will be diagnosed with AjD in cancer and 20 participants will be diagnosed with AjD in the context of either ALS, MS, PD, or IPF. Randomization for participants with AjD in cancer will be stratified based upon “acute” (symptom duration <6 months) versus “persistent” (symptom duration >6 months) AjD as well as concomitant selective serotonin reuptake inhibitor (SSRI) and / or psychotherapy use (yes / no). Randomization for participants with AjD in the other, noncancer illnesses will be stratified based upon illness (ALS or MS or PD or IPF).Randomization will also be constrained such that no more than 15% of participants will have had prior psychedelic use (use within 1 year of Screening will be exclusionary).

[0079] The study consists of 3 periods: a Screening Period of up to 28 days, immediately followed by the Dosing Day (Day 0), and a Follow-Up Period of 42 days (6 weeks) after dosing.

[0080] Screening Period (Day -28 through Day -1):

[0081] The Screening Period begins when a participant provides written informed consent prior to any study-related assessments.52 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0082] Participants with a pre-existing diagnosis of cancer, ALS, MS, PD, or IPF will be screened for eligibility, including confirmation of a diagnosis of AjD with depressed mood, or mixed anxiety and depressed mood. Diagnosis will be made using the SCID-5-CT. Symptom severity will be assessed using the Patient Health Questionnaire (PHQ-9) and MADRS total score.

[0083] Initial screening must be completed, and preliminary eligibility confirmed before conducting preparatory sessions. Participants will complete 2 preparatory sessions in person with their Session Monitor(s) at the clinic. The sessions will be recorded and will occur over a 2-week period, with the first session scheduled around Day -14 and the second session scheduled between Day -7 and Day 0. Preparatory sessions are considered supportive, without formal or manualized psychotherapy procedures.

[0084] Entry Interviews:

[0085] Approximately 30 to 40 individuals will be given the option to participate in an entry interview. The goal of the entry interview is to understand and describe important symptoms and impacts experienced by individuals with AjD and to cognitively debrief the PGI-S and PGI-C items. Participants who are eligible for the study or who do not meet the eligibility for the study after Visit 1 will be eligible to participate in the entry interview. As applicable, the entry interview will be conducted prior to dosing.

[0072] Dosing Day (Day 0):

[0073] Pre-dose assessments will be completed on Day 0 to ensure continued eligibility and suitability of participants for dosing. Eligible and suitable participants will be randomized to 1 of 2 dose levels of compound 1 (30 mg or 1.5 mg, when calculated in zwitterion form).

[0074] Dosing with study medication will occur on Day 0 after all pre-dose assessments and procedures have been completed. The study drug will be prepared and administered as a SC injection. While the post-dose acute experience phase of the dosing session is expected to last approximately 4-5 hours, post-dose session monitoring will last for at least 8 hours post-dose and will be supported by 2 qualified Session Monitors. The post-dose session monitoring period will be video recorded for training and adherence monitoring. All safety surveillance mechanisms are consistent with regulatory guidance regarding interventional studies with psychedelic agents.53 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0075] After dosing, participants will remain in the clinic for 8 hours under general observation for post-dose assessments, routine safety monitoring, and discharge readiness evaluation.

[0076] The discharge readiness evaluation will begin at 3 hours post-dose and evaluations performed hourly through the 8-hour discharge time point. The discharge readiness evaluation will be performed by clinical examination and will include an assessment of the participant’s psychiatric and physical status and associated health parameters including vital signs, and the status of any treatment-emergent AEs.

[0077] Once confirmed ready for discharge, participants will be allowed to go home and must be escorted by a trusted friend, family member, or caregiver. If the participant’s clinical condition does not warrant discharge at the 8-hour post-dose timepoint, the participant will be managed under standard of care until ready for discharge.

[0078] Follow-Up Period (Dav 1 to Dav 42):

[0079] The Follow-Up Period consists of in-clinic and / or remote safety and efficacy assessment visits on Days 1, 7, 14, 28, and 42 per the Schedule of Activities (SoA).

[0080] During the Follow-Up Period, post-dose follow-up sessions will be conducted on Day 1 and on Day 7 by the Lead Session monitor (LSM). Efficacy ratings will be completed prior to each follow-up session.

[0081] At the completion of the study, or upon early discontinuation, the Investigator should ensure there is a plan in place for appropriate participant care and adequate referral if needed.

[0082] Exit Interviews:

[0093] At the conclusion of the study, approximately 30 semi-structured concept elicitation exit interviews of a randomly selected subset of study participants representing participants from each AjD specifier group, will be completed by third-party interviewers who are experienced health researchers skilled in qualitative research. Each interview will be recorded and later transcribed to allow for qualitative analyses of the results.

[0094] The schedule of activities for this trial is shown in Table 2.54 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)Table 2. Schedule of Activities55 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)aScreening assessments may be performed over more than 1 day, as long as they are conducted within the Screening window. For those participants who also require that PFTs is performed for eligibility, this should be done after most other criteria have been assessed and preliminary eligibility has been confirmed.bParticipants who discontinue study participation prior to Day 42 should return to the clinic to complete the Day 42 (V9) EOS assessments.cCentral Eligibility Review will be completed by the Worldwide CAT and MM teams and will provide a determination of eligibility to proceed to the Investigator. Note that this review may take up to 7 business days and should be received by the Investigator prior to V2.dComplete physical examination (at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems) at Screening. A brief symptom-directed physical examination will be conducted thereafter.eA serum pregnancy test is performed at Screening and Day 42. A urine pregnancy test is performed at Day 0.fHeight and weight will be measured, and BMI will be calculated at Screening (Visit 1) only. Only weight will be measured at subsequent visits indicated.gAE assessment includes assessment of injection site reactions, to be done prior to discharge on Day 0 and at each follow-up visit.hOxygen saturation and manual respiratory rate will only be measured during Screening and on Day 0 (pre- and post-dose).1On Day 0, vital signs are to be assessed pre-dose, and 1, and 3 hours post-dose. After the 3-hour timepoint, additional hourly assessments of vital signs will be performed through at least 8 horns post-dose or longer until the participant is deemed ready for discharge. Measurement of blood pressure while participants are in a standing position will only be assessed at Screening.56 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)JOnly for those participants requiring PFTs necessary to establish eligibility for the study PFTs will include spirometry (FVC, FEV1) and DLCO. Note that spirometry performed within 2 months of Screening will be considered acceptable for evaluation of eligibility.kECGs will be recorded in the supine position, allowing 5 minutes of rest, and before performing any venipuncture. On Day 0, ECGs are to be assessed pre-dose, 1-, 3-, 4-, 5-, 6-, 7- and 8-hours post-dose. Triplicate ECGs will be obtained at all Day 0 timepoints.1The C-SSRS “baseline / screening” version will be administered at the Screening VI, while the C-SSRS “since last visit” version will be administered thereafter.111The PCRS should always be administered prior to any efficacy assessments (i.e., PHQ-9, MADRS or HAM- A).nWhere applicable, the PHQ-9 is to be administered before the MADRS and the MADRS to be administered before the HAM-A.° The 24-hour recall version of the MADRS (MADRS-24hr) will be used.pThe PGI-C and PGI-S will be administered by the Site Rater via telephone.qThe MEQ-4 should be completed after the acute study drug effects subsided, when the participant is stable and oriented in time and space. This assessment will be completed no earlier than 4 horns post-dose and prior to discharge.rPreparatory sessions are anticipated to last approximately 60-90 minutes. The first session is recommended to be scheduled by Day -14 and the second session between Day -7 and Day -1. Additional preparatory sessions may be conducted at the discretion of the Investigator and / or LSM.sThe participant will be monitored by 2 Session Monitors for at least 8 hours after the study drug administration.1The first post-dose follow-up session may be completed remotely (preferably by videoconference) by the LSM at any time between Day 1 (V4) and Day 4 (V5) inclusive. The second follow-up session may be done in person or remotely on Day 7. Where applicable, post-dose follow-up sessions should be scheduled to be conducted after efficacy assessments (i.e., MADRS, HAM-A) have been completed. Additional follow-up sessions may be conducted at the discretion of the Investigator and / or LSM.uAssessments will be conducted hourly between 3 -hour and 8-hour post-dose timepoints inclusive. Discharge may only occur at the 8-hour post-dose timepoint (or thereafter per Investigator judgment, if the participant is not ready for discharge at the 8-hour timepoint). C-SSRS and BPRS+ will be completed only once at the 8- hour timepoint.vThe Central Rater will complete the blinding assessment at Day 7. The participant and the Site Raters will complete the blinding assessment at Day 42.wEntry interviews, which will be completed remotely in a subset of participants, including both eligible and screen failed participants, should be completed prior to dosing or within 7 days of screen fail (at VI or V2). Exit interviews, which will be completed in a subset of study participants, are targeted ideally for completion within 7 days of the EOS visit.Abbreviations: ADNM-20 = Adjustment Disorder New Module 20; AE = adverse event; ALS = amyotrophic lateral sclerosis; BMI = body mass index; BPRS+ = Brief Psychiatric Rating Scale - positive symptoms subscale; CAT = clinical assessment training and surveillance; CGI-C = Clinical Global Impression-Change; CGI-S = Clinical Global Impression-Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; DLCO = diffusing capacity for carbon monoxide; DS-II = Demoralization Scale Version II; ECG = electrocardiogram; EOS = End of Study; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GAD-7 = Generalized Anxiety Disorder 7-Item; HADS = Hospital Anxiety and Depression Scale; HAM-A = Hamilton Anxiety Rating Scale; LSM = Lead Session Monitor; MADRS = Montgomery-Asberg Depression Rating Scale; MEQ-4 = Mystical Experience Questionnaire 4-item; MM = medical monitoring; MMSE = mini mental-state examination; PCRS= Placebo-Control Reminder Script; PFT = pulmonary57 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) function testing; PGIC = Patient Global Impression-Change; PGI-S = Patient Global Impression-Severity; PHQ-9 = Patient Health Questionnaire-9; PROMIS-SF = Patient- Reported Outcome Measurement Information System-Short Form; SCID-5-CT = Structured Clinical Interview for DSM-5-TR Axis I Disorders (Clinical Trial Version); V = visit.5.1.3.1 Scientific Rationale for Study Design

[0095] The study is a randomized, double-blind, dose-controlled, single dose study of 30 mg compound 1 compared to 1.5 mg compound 1 for the treatment of AjD with depressed mood or mixed anxiety and depressed mood in participants with cancer, ALS, MS, PD, or IPF. Randomized, double-blind, parallel designed studies are the current standard for short-term efficacy trials for major depressive disorder. A low dose of compound 1 will be used as a control rather than placebo to minimize the likelihood of functional unblinding of site staff and participants and is common in psychedelic clinical trials.

[0096] The effects of compound 1 in 80 participants with AjD with depressed mood or mixed anxiety and depressed mood due to cancer will be assessed given previous data indicating that treatment with other psychedelics may be useful to reduce depressive symptoms in this population. Additionally, the effects of compound 1 will also be assessed in 20 participants with AjD with depressed mood or mixed anxiety and depressed mood due to other medical illnesses including ALS, MS, PD, or IPF. This subgroup of participants with medical illnesses other than cancer will be utilized to explore if compound 1 has a differential effect in this population compared to participants with AjD in cancer.

[0097] The illnesses selected for this study are intended to broadly represent illnesses across therapeutic areas including autoimmune, neurological, and respiratory illnesses. These illnesses have been chosen based upon the prevalence of AjD or depressive symptoms within the patient population and as well as an anticipated lack of neuropsychiatric or cardiovascular illness-related comorbidities which would make treatment with a psychedelic contraindicated. Regardless, eligibility criteria for all participants have been shaped to exclude participants with comorbid neuropsychiatric, cardiovascular, or other illnesses which could pose a safety risk.

[0098] Participants with a life expectancy of >6 months have been included to limit potential confounding safety issues or inability to complete assessments due to functional impairment arising from their illness. Future studies may explore the effect of compound 1 on patients with life expectancy of <6 months.58 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0099] Participants will be required to meet DSM-5-TR diagnostic criteria for AjD for >4 weeks. Allowances will be made to extend eligibility to include participants who initially present with AjD under DSM criteria (e.g., per DSM-5-TR) but who are excluded solely because their depressive symptoms meet the threshold for MDD / major depressive episode (MDE) (i.e., patients who have >5 symptoms). By extending the population, the study will include the clinically relevant spectrum of participants developing moderate-to-severe depressive symptoms in reaction or adjustment to the study-defined stressor / medical illness and who warrant treatment but would otherwise be excluded due to rigid adherence to current DSM-5-TR criteria. While the DSM-5-TR does not specify a minimum time frame for the duration of symptoms to diagnose AjD, requiring a minimum time of at least 4 weeks ensures that symptoms are sufficiently persistent and clinically impairing, and is consistent with the look back period for the PHQ-9 which is utilized to determine the threshold of disease severity for eligibility and for the MADRS which is utilized as the primary outcome measure.

[0100] Clinician-rated outcomes measures are the current standard for assessing efficacy in antidepressant trials. The FDA has accepted the MADRS as a primary endpoint to support indications in major depressive disorder.

[0101] To reduce variability and further minimize bias, the primary efficacy measure will be completed by a Central Rater, who will be blinded to treatment allocation and all other study assessment results.

[0102] Based on demonstrated potential long-term and durable therapeutic effects, unlike conventional pharmacotherapy, psychedelic therapy is commonly dosed in a single or infrequent dosing session. The primary endpoint in this study will be at Day 7 to assess the effect at a relatively early timepoint proximal to treatment. Additional efficacy assessments at Day 1, and Day 14 through Day 42 will assess early effect and durability of the effect beyond Day 7.

[0103] Consideration for the study design includes review and feedback from the FDA, as well as information provided in the FDA’s draft guidance for industry on psychedelic drugs.5.1.3.2 Justification for Dose

[0104] In accordance with FDA guidelines for estimating the safe starting dose in initial clinical trials and using the no observed adverse effect level (NOAEL) established in compound 1 non-clinical safety program, the Phase 1 trial in healthy adult volunteers applied a 10-fold safety margin for the first cohort dosed with 5.0 mg of compound 1. In the Phase 159 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) trial, the dose was increased based on the data collected during the trial and evaluated by a safety review committee which permitted dosing to continue up to 40 mg compound 1. The trial included 9 participants dosed at 30 mg, 6 at 34.5 mg, and 3 at 40 mg compound 1. All doses were found to be generally safe, with no serious AEs, no clinically significant vital signs, clinical laboratory, electrocardiogram (ECG) findings, or adverse signs and symptoms of serotonergic hyperactivity, including seizures at doses up to and including 40 mg compound 1.

[0105] Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestation of serotonin toxicity. The risk of developing serotonin syndrome after a therapeutic dose of a prescribed serotonergic agent in humans is unknown but thought to be low. The risk of developing serotonin syndrome with the single dose administration of compound 1 is anticipated to be low, due to the rapid elimination of compound 1 and 4-OH-DiPT from systemic circulation, and based on its safety profile as demonstrated in the Phase 1 clinical trial in healthy adult volunteers. The risk of developing adverse signs and symptoms of serotonergic hyperactivity, including seizure, at the planned dose of 30 mg compound 1 in Phase 2, is expected to be very low based on data from the completed Phase 1 trial.

[0106] In the Phase 1 trial, single SC administration of compound 1 was well tolerated in healthy adult subjects up to a dose of 30 mg. The 35 mg and 40 mg compound 1 doses were not considered as well tolerated due to the high intensity of the psychedelic experience, which was reflected in the Drug Effects Questionnaire scores, and was associated with the occurrence of transient, mild to severe, acute AEs characterized as challenging experiences. Challenging experiences have been described to include affective (e.g., panic or fear, depressed mood, anger, dysphoria), cognitive (confusion, feelings of losing sanity, delusions, dissociation, depersonalization), and physiological (e.g., nausea / emesis, heart palpitation, sympathetic system response) symptoms and have been reported to occur with psilocybin and other classic hallucinogens. Challenging experiences can be mitigated by careful screening of study subjects, adequate pre-dose preparation, and close monitoring with psychological support in controlled settings.

[0107] A dose-related increase in the frequency of Mystical Experience Questionnaire (MEQ) (assessment of individual episodes of mystical experience) responders was observed, with 66.7%, 83.3%, and 100% of subjects in the 30 mg, 35 mg, and 40 mg compound 160 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) treatment groups, respectively, having a “complete” mystical experience (defined as >60% of MEQ total score) predictive of clinical efficacy, based on MEQ total scores.

[0108] The overall safety profile of compound 1 appears to be consistent with those reported for other 5-HT agonists, including psilocybin, and treatment-emergent adverse events (TEAEs) observed are likely related to its mechanism of action. No new safety signals were observed compared to the non-clinical toxicology findings for compound 1 and the established clinical profile for psilocybin and pharmacodynamic effects observed at the >30 mg Compound 1 dose level are possibly predictive of clinical efficacy in depressive symptoms reduction.

[0109] Taking into consideration both safety and pharmacodynamic data, the dose of 30 mg compound 1 was selected for this study in participants with AjD due to medical illness. The active dose-control of 1.5 mg compound 1 was selected to address concerns over the use of a traditional placebo control and is anticipated to be a subperceptual dose of compound 1.5.1.4. Study Population

[0110] Approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.5.1.4.1 Inclusion Criteria

[0111] Participants are eligible to be included in the study only if all of the following criteria apply:1. Is male or female aged 18 to 80 years inclusive, at the time of signing the informed consent.Disease Characteristics2. Has a >4 week history of AjD as defined by DSM-5-TR with either depressed mood, or mixed anxiety and depressed mood specifiers, and confirmed by the SCID-5-CT with evidence that the mood disorder was instigated by one of the medical illnesses (e.g., diagnosis, management, recurrence, prognosis) as per Criterion 3 below.3. Has one of the following medical illnesses as determined by medical records: a) Cancer: diagnosis of Stage 0 through Stage 4 (inclusive), or a cancer not formally stagedMust be at least 4 weeks post-surgery at study Screening. If currently receiving a course of radiotherapy or cytotoxic chemotherapy, the day of dosing (Day 0) must be61 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) scheduled at least 4 weeks after completion of the most recent radiotherapy or cytotoxic chemotherapy cycle. If the treatment course is not yet complete, the next cycle should be planned to begin no earlier than 1 week after day of dosing (Day 0). b) ALS: sporadic or familial ALS diagnosed by the revised El Escorial criteria as possible, probable, laboratory-supported probable, or definite ALS. In the event that this previous method for diagnosis is not available a diagnosis by the Gold Coast diagnostic criteria will suffice. c) MS: diagnosed by revised McDonald criteria as assessed and documented within 2 years of Screening. d) PD: idiopathic PD diagnosed by Movement Disorder Society clinical diagnostic criteria with a Hoehn and Yahr Stage 1-3 inclusive during an "off1state. e) IPF: diagnosed according to the most recent guideline on IPF diagnosis and management released by the American Thoracic Society, the European Respiratory Society, Japanese Respiratory Society and the Latin American Thoracic Society.4. In the opinion of the Investigator, has a projected life expectancy of >6 months.5. In the opinion of the Investigator, is sufficiently ambulatory and capable of self care, as necessary to participate in and complete required study procedures.6. Normal cognition confirmed by Mini-Mental State Examination (MMSE) score >247. Has a PHQ-9 score of >10 at Screening (Visit 1) and MADRS score of >20 (at Visit 1 and Visit 2).8. Is willing to delay the use of any psychotropic pharmacotherapy regimens, including antidepressants, or psychotherapy until the end of study (Day 42) unless already on a stable regimen of selective serotonin reuptake inhibitors (SSRIs) serotonin partial agonist reuptake inhibitors (SPARIs), serotonin modulators and stimulators (SMSs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), atypical antidepressants, or psychotherapy for 30 days prior to Screening (i.e., no changes to regimen are allowed 30 days prior to Screening and until the end of study).Sex, Contraceptive / Barrier Requirements, and Breastfeeding1. If female:62 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) a) Has a negative serum pregnancy test at Screening and negative urine pregnancy test on Day 0 prior to study drug administration. Testing is not required for participants who have documentation confirming their status as non-childbearing potential. b) Is not currently breastfeeding. c) Is a woman of non-childbearing potential, or if a woman of childbearing potential agrees to use appropriate contraceptives. d) Must agree to refrain from donating oocytes from Screening up to at least 90 days after study administration.2. If male: a) Must be surgically sterile (>30 days since vasectomy with no viable sperm), abstinent from heterosexual intercourse, or if engaged in sexual relations with a female of childbearing potential, the participant and his partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective contraceptive method as assessed by the Principal Investigator (PI), from Screening until study completion, including the Follow-Up Period, for at least 90 days after study drug administration. Male participants whose female partner is post-menopausal, and participants who are abstinent as part of their usual lifestyle will also be eligible. b) Must agree to refrain from donating sperm from Screening until study completion, including the Follow-Up Period, and for at least 90 days after study drug administration.NOTE: The method of contraception agreed to must be documented for each participant.Informed Consent1. Is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.Other Inclusion Criteria1. In the opinion of the Investigator, is capable of understanding, and is willing and able to comply with all the conditions and requirements of the study.63 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)2. Has an adult (e.g., family member, caretaker) to escort them home from the dosing session.5.1.4.2 Exclusion Criteria

[0112] Participants are excluded from the study if any of the following criteria apply:Medical Conditions1. Has current MDD / MDE that is determined to be independent of the instigating medical illness or stressor (as defined in the list of included medical illnesses per Inclusion Criterion 3). a. Any history of MDD not in remission for at least 6 months prior to the onset of the stressor is also excluded. b. A worsening of a pre-existing MDD (not in remission) due to the instigating illness / stressor is also excluded.2. Has a history of or active central nervous system (CNS) malignancy.3. Has a significant risk of suicide according to the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or Visit 2, or has attempted suicide. a. Acute suicidality as evidenced by answering “yes” for Question 4 or Question 5 on the C-SSRS, indicating active suicidal ideation with any intent to act at Screening or Visit 2. b. History of or active suicidal behavior such that a determination of “yes” is made on the Suicidal Behavior section of the C-SSRS for “Actual Attempt,” “Interrupted Attempt,” “Aborted Attempt,” or “Preparatory Acts or Behavior.”4. History of bipolar disorder, schizophrenia, schizoaffective disorder, hallucinations, and / or psychotic disorder.5. History of borderline personality disorder, or first-degree family history of psychosis or bipolar disorder.6. Has a medically significant condition rendering unsuitability for the study (e.g., neurologic disorders [other than those intended for the study per Inclusion Criterion 3], uncontrolled diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure [e.g., creatinine clearance <30 mL / min],) or contraindications to SC dosing in the opinion of the Investigator.64 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)7. Participants with ALS, IPF, history of treatment of thoracic cancer or history of surgical resection of lung cancer, as well as participants with history of pulmonary disease, reported dyspnea at rest or on exertion who meet any of the following parameters: Forced vital capacity (FVC) <60% of the predicted normal; Forced expiratory volume in 1 second (FEV1) <60% of the predicted normal; FEV1 / FVC ratio <0.7; Diffusing capacity for carbon monoxide (DLCO) <60% of the predicted normal; Participants with a supplemental oxygen requirement; Resting oxygen saturation <92% on ambient air at Screening or Day 0 (pre-dose); Participants with a history of clinically significant dysarthria, difficulty swallowing, aspiration, or bulbar / pseudobulbar symptoms of neuromuscular disease; Participants with documented pulmonary hypertension; Participants who are currently administered bilevel positive pressure ventilation or noninvasive positive pressure ventilation for sleep or daytime use (Pulmonary function testing (PFT) (including spirometry) performed within 2 months of Screening will be accepted for evaluation of eligibility under this criterion).8. Participants with IPF who: a. Experienced an IPF exacerbation or hospitalization within 6 months of Day 0. b. Have a current upper respiratory tract infection, or had an upper respiratory tract infection within 6 weeks of Day 0.9. Has active or history of seizures other than childhood febrile seizures.10. Abnormal QT interval prolongation at Screening or Day 0 prior to dosing, or has a history of QTc prolongation (corrected QT interval using Frederica’s formula [QTcF] >450 ms) and / or additional risk factors for torsade de pointes (e.g., family history, electrolyte derangement, inherited long QT syndrome), and / or use of concomitant medications that prolong the QT / QTc interval (e.g., citalopram >40 mg / day).11. Current uncontrolled hypertension or clinically significant blood pressure abnormality at Screening or pre-dose on day of dosing. This includes, but is not limited to, the following, measured in the supine position (after at least 5 minutes rest): systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg. If the initial65 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) blood pressure is >140 / 90 mmHg, up to 3 additional attempts during the Screening Visit are allowed.12. Has orthostatic hypotension at Screening defined as a decrease in systolic blood pressure of >20 mmHg or diastolic blood pressure of >10 mmHg within 3 minutes of standing from the supine position.Prior / Concomitant Therapy1. Has used contraindicated medications / agents.2. Has initiated new psychotherapy (cognitive behavioral therapy) within 30 days prior to Screening. No changes to stable psychotherapy within the 30 days prior to Screening are allowed.3. Has had administration of electroconvulsive therapy (ECT) within 90 days prior to Screening and / or is expected to receive ECT before the Day 42 Visit.4. Has had administration of transcranial magnetic stimulation (TMS) within 30 days prior to Screening and / or is expected to receive TMS before the Day 42 Visit.5. History of or active substance use disorder (including alcohol) in the 12 months prior to Screening, or positive urine drug screen for illicit drugs or drugs of abuse at Screening and / or Day 0. Any positive urine drug test at Screening will be reviewed with participants to determine the pattern of use and medical justification for use, and discussed with the Medical Monitor to determine whether the participant should continue with screening activities. A negative drug screen by Day 0 for illicit or drugs of abuse is required (with the exception of prescribed medications or cannabinoids).6. Known sensitivity or intolerance to hallucinogenic or psychedelic substances (not including cannabis products), or potential rescue medications (e.g., short-acting benzodiazepines or standard of care for nausea or vomiting) as reported by the participant and / or determined by the Investigator.7. Has had exposure to another investigational medication or device within 30 days or 5 half-lives (if known) prior to Screening.Other Exclusion Criteria1. Is a participant who, as determined by the Investigator, is not otherwise considered suitable for the study (i.e., physical, logistical, or emotional impact of the medical illness or treatment regimen incompatible with study schedule and / or study treatment,66 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) extreme or significant complicating comorbidities (with the exception of the AjD instigating medical illness), past or current trauma (including current experience of post-traumatic stress disorder), social stressors / instability and / or personal circumstances and behavior that might be incompatible with the establishment of rapport or safe exposure to study treatment).2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling), or any person who may consent under duress.3. Is a participant who withdraws consent prior to randomization.5.1.5. Study Intervention and Concomitant Therapy

[0113] Study interventions are all pre-specified, investigational medicinal products, and other interventions (e.g., behavioral) intended to be administered to the study participants during the study conduct.5.1.5.1 Study Intervention Administered

[0114] The drug product, compound 1 for Injection is a sterile lyophilized powder supplied in a vial ready for reconstitution with an aqueous solution, compound 1 Diluent. Table 3 provides an overview of the interventions and relevant components. 36 mg of the HC1 salt of compound 1 was provided in a vial. Diluent was added to the HC1 salt of compound 1 to provide a solution containing 33 mg of solubilized compound 1 (calculated as the free base). The dose taken up from the vial for administration to the subject contained 30 mg compound 1 (calculated as the free base).Table 3. Study Intervention Administered67 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1.5.2 Assignment to Study Intervention

[0115] All participants will be centrally assigned to 1 of 2 treatment arms and randomized to study drug using an interactive response technology (IRT). Randomization will use permuted blocks, and will stratify participants as follows:• Participants with cancer will be stratified by “acute” (symptom duration <6 months) versus “persistent” (symptom duration >6 months) AjD and by concomitant selective serotonin reuptake inhibitor (SSRI) and / or psychotherapy use (yes / no) and will assign participants in an equal ratio to both arms.• Participants with ALS, MS, PD, or IPF will be stratified by their medical illness.

[0116] Randomization will be constrained based upon stratification factors with 80 participants being randomized within the cancer group and 20 participants within the noncancer, other medical illness group. Randomization will also be constrained such that no more than 15% of participants will have had prior psychedelic use.68 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0117] Before the study is initiated, the log-in information and directions for the IRT will be provided to each site.5.1.5.3 Blinding

[0118] Participants will be randomly assigned in a 1 : 1 ratio to receive study drug. Investigators and participants will remain blinded to the assigned study drug throughout the course of the study. To maintain this blind, an independent, unblinded study staff / pharmacy representative will be responsible for the reconstitution and dispensation of all study drugs.

[0119] The Sponsor will assign independent, unblinded study monitors to review unblinded study drug records at the site(s) to monitor site drug accountability. This unblinded study monitor will be different than the study monitor assigned to review clinical data. In addition, in the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study drug records at the site(s) to verify that randomization / dispensing has been conducted accurately.5.1.5.3.1 Unblinding

[0120] The Investigator together with the Sponsor may decide to unblind the participant’s treatment allocation during the course of the study for reasons including the participant’s safety, to make decisions on the participant’s treatment, or other reasons as per the discretion of the Investigator and / or Sponsor.

[0121] If the blind needs to be broken for a Suspected Unexpected Serious Adverse Reaction (SUS AR) event by the Sponsor (or designee), the blind should only be broken for that specific participant. All effort should be made to ensure that the blind is maintained for persons responsible for the ongoing conduct of the study (such as the management, monitors, Investigators) and those responsible for data analysis and interpretation of results at the conclusion of the study, such as biometrics personnel.

[0122] Unblinded information should only be accessible to those who need to be involved in the safety reporting to national competent authorities, Ethics Committees and DSMBs, or persons performing ongoing safety evaluations during the study.5.1.5.4 Prior and Concomitant Therapy5.1.5.4.1 Prior Therapy

[0123] All medications (prescription and over-the-counter [OTC]) taken within 3 months of study Screening will be recorded along with reason for use, dates of administration, and69 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) dosage information (including dose and frequency). In addition, any psychiatric interventions (e.g., medications, psychotherapy or support) used since development of signs or symptoms of depression or anxiety will also be recorded.

[0124] Any historic use of psychedelic drugs will be recorded.5.1.5.4.2 Concomitant Therapy

[0125] All medications (prescription and OTC) taken starting from the study Screening Period through EOS will be recorded along with reason for use, dates of administration, and dosage information (including dose and frequency). In addition, nonpharmacological psychiatric interventions will be recorded during the study, including the use of grounding techniques used during the dosing sessions.

[0126] Participants should not initiate new psychotropic medications or additional psychiatric intervention while in the study unless in the Investigator’s judgment the participant is becoming suicidal or experiencing significant deterioration.5.1.5.4.1 Prohibited Therapy

[0127] The medications described in Table 4 are prohibited or restricted according to the regimen and / or within the timeframes indicated. This table includes those that are exclusionary as part of eligibility assessments, in addition to restrictions throughout the duration of the study.Table 4. Prohibited or Restricted Medications70 Of 1044925-5827-3149.1Atorney Docket No.: 145737-0182 (008WO)71 Of 1044925-5827-3149.1Atorney Docket No.: 145737-0182 (008WO)72 Of 1044925-5827-3149.1Atorney Docket No.: 145737-0182 (008WO)73 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)Abbreviations: 5-MeO-DiPT = 5-methoxy-diisopropyltryptamine; 5-MeO-DMT = 5-methoxy-N,N- Dimethyltryptamine; DMT = N,N -Dimethyltryptamine ; IV = intravenous; LSD = lysergic acid diethylamide; MAO = monoamine oxidase; MDA = 3,4-methylenedioxyamphetamine; MDMA = 3,4- Methylenedioxymethamphetamine; NMDA = N-methyl-D-aspartate; QD = once daily; SARI = serotonin antagonist and reuptake inhibitor; SMS = serotonin modulator and stimulator; SNRIs = serotonin-norepinephrine reuptake inhibitors; SPARI = serotonin partial agonist and reuptake inhibitor; SSRIs = selective serotonin reuptake inhibitors.74 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1.5.5 Rescue Medication During and After the Dosing Session

[0128] Non-pharmacologic interventions should be initiated to manage participant anxiety or agitation, with medication administration reserved for those who do not respond to psychological support and management. Rescue medication for acute AEs associated with the use of hallucinogen psychedelics, also known as “challenging experiences” or “bad trips” may be used if needed under the supervision of a responsible physician during or after the dosing session. The use of rescue medications should be employed only after other nonpharmacological techniques (e.g., grounding techniques) have been used by trained Session Monitors. The decision to medicate a participant will depend on whether the Session Monitors and the responsible physician determine that they can maintain the safety of the participant and others without medical intervention• Benzodiazepine anxiolytics are the pharmacological intervention of choice in case of acute psychological distress (e.g., medications such as lorazepam or alprazolam that have a rapid onset, a short time until peak plasma concentration, and a short duration of therapeutic action); the oral route is preferable because intravenous injection procedures may further exacerbate the participant’s anxiety.• Antipsychotic medications (e.g., risperidone) should be available if an AE escalates to unmanageable psychosis. Antipsychotic medications should be administered at doses as per local guidelines accounting for the participants’ comorbidities and potential side effects as per Investigator’s clinical judgment.

[0129] Standard of care for management of gastrointestinal AEs (e.g., nausea or vomiting) may also be used during the dosing session at the discretion of the responsible physician if required.

[0130] Information for how to manage participants during difficult psychological states are detailed in the Session Monitor’s Manual.5.1.5.5.1 Benzodiazepine Use in Special Populations

[0131] If non nonpharmacological interventions are ineffective or otherwise inappropriate, benzodiazepines may be used. In particular, in participants with IPF, neuromuscular disease (ALS, MS, PD), or thoracic cancer, benzodiazepine administration must be closely monitored by the Investigator or another physician. A licensed physician certified in advanced cardiovascular life support (ACLS) must be available on-site and able to respond in the event of an emergency during benzodiazepine administration in these populations. Low starting75 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) doses are essential to minimize the risk of sedation, respiratory depression, and other AEs associated with benzodiazepine use. Short-acting benzodiazepines (e.g., lorazepam, and oxazepam) are generally preferred over long acting agents (e.g., diazepam, chlordiazepoxide, and clonazepam) to reduce accumulation and risk of prolonged effects. The following examples of recommended initial and maximum doses of short-acting benzodiazepines include:• Lorazepam: start at 0.5 mg; maximum dose 2 mg / day• Oxazepam: start at 5 mg; maximum dose 15 mg / day

[0132] If the initial dose was ineffective but well tolerated, it can be repeated every hour as needed (for lorazepam and oxazepam) until the maximum dose is reached.

[0133] To ensure participant safety, the Investigator must obtain vital signs (blood pressure, heart rate, respiratory rate, and temperature) and oxygen saturation before administration of benzodiazepines, and immediately after every dose. Additionally, vital signs and oxygen saturation need to be taken every 15 minutes during the first hour, and then at least every hour until the participant is deemed ready for discharge. It is essential to monitor regularly for sedation, excessive sleepiness, confusion, cognitive decline, increased dyspnea and other AEs.

[0134] The same safety monitoring applies in case of a second administration of benzodiazepines. The Investigator or other qualified healthcare professional must be in room during the administration of benzodiazepines and for an appropriate amount of time afterwards.

[0135] Participants must not be discharged until discharge criteria are met. This includes consideration of any residual effects from rescue medications such as benzodiazepine administration (e.g., respiratory depression, excessive sedation or confusion, balance difficulties).5.1.5.6 Escalation of Care

[0136] A participant who displays abnormal vital sign measurements or complaints of dyspnea should be closely monitored and the Investigator should provide adequate escalation of care.

[0137] Participants who need additional follow-up include (but are not limited to):• Those with dyspnea, increased respiratory rate, or increasing oxygen requirements.76 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)• Those with lethargy or somnolence, in the opinion of the Investigator or who have PD with increased daytime sleepiness.• Those who have received benzodiazepines.• Those who experience an aspiration event.

[0138] Initial evaluation will be performed by a licensed physician certified in ACLS within 15 minutes of the event. If clinically indicated, collection of vital signs (blood pressure, heart rate, respiratory rate, temperature), oxygen saturation and ECG should be done and repeated as necessary at the discretion of the Investigator.

[0139] If oxygen saturation is decreased (<92%), supplemental oxygen at up to 6 L / min by nasal cannula to maintain oxygen saturation >92% should be considered along with urgent medical evaluation, as needed. If used, the dose of supplemental oxygen must be recorded (i.e., flow rate and delivery device). The Investigator should re-evaluate the participant’s oxygenation status to determine whether the level of oxygenation is appropriate or if the treatment plan needs to be adjusted. Medications that are considered necessary for the participant’s safety and well-being may be given at the discretion of the Investigator.

[0140] Any subject who meets any of the criteria listed below will be evaluated for referral / transfer to secondary / emergency care based on clinical evaluation of the participant’s state and symptoms:• Respiratory rate >30 breaths per minute• Heart rate >130 beats per minute• Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg (unless this is normal for the participant)• Oxygen saturation <92% or central cyanosis (if the participant has no history of chronic hypoxia)• A substantial respiratory effort, particularly if accompanied by exhaustion• Altered level of consciousness• Stridor• ECG suggesting a cardiac arrhythmia or myocardial infarction• High body temperature, especially if >38.5°C77 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0141] In addition, any participants in a special population (defined as participants with IPF, ALS, MS, PD, or thoracic cancer) who meet any of the above must be immediately referred to secondary / emergency care.

[0142] Events related with escalation of care and the procedures to treat them should be appropriately documented in the electronic case report form (eCRF) as adverse events of special interest (AESIs).5.1.6. Study Assessments and Procedures

[0143] Unless otherwise indicated, the Investigator or designated study personnel will perform all assessments. The Investigator will ensure that assessments are completed by appropriately trained or qualified personnel.

[0144] All assessments and procedures will be performed throughout the study as noted in the SoA.5.1.6.1 Rater Roles5.1.6.1.1 Central Rater

[0145] To reduce variability and minimize bias, both primary and secondary study efficacy measures will be completed by a Central Rater (MADRS and Hamilton Anxiety Rating Scale [HAM-A]). The Central Rater will also administer the Placebo-Control Reminder Script (PCRS) prior to administering the MADRS and HAM-A.

[0146] The Central Rater will be blinded to treatment allocation and all other study assessments’ results. The Central Raters will not have access to or review participant records, including screening scales and safety information.

[0147] Efficacy data will be centrally reviewed and monitored for accuracy and quality as outlined in the study specific Data Surveillance Plan. The study specific Clinical Assessments Data Surveillance Plan describes the qualifications, selection, training, and oversight of the Central Raters.5.1.6.1.2 Clinical Site Raters

[0148] Clinical Site Raters will be responsible for administering those clinician assessments not performed by the Central Rater, and patient-reported outcomes. During the remote visits, the Clinical Site Raters will facilitate the collection of patient-reported outcomes via telephone call. During the Screening Period, the Site Rater will administer the PCRS prior to administering the PHQ-9.78 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0149] The Clinical Site Rater will be blinded to treatment allocation.

[0150] The study specific Clinical Assessments Data Surveillance Plan describes the qualifications, selection, training, and oversight of the clinical site raters.5.1.7. Screening / Baseline Assessments and Procedures

[0151] The Screening Visit is to occur within 28 calendar days prior to the study intervention. An ICF must be signed by participants before any study -related assessments are performed. After signing the ICF, each participant will be screened to ensure eligibility for the study.

[0152] The general eligibility assessments include a review of the inclusion and exclusion criteria, collection of demographic information, medical and family history, and screening for drugs of abuse and alcohol use. Eligibility will be determined during the Screening Period and will involve centralized eligibility review. Participants will be randomized on Day 0.5.1.8. Efficacy Assessments

[0153] Planned timepoints for all efficacy assessments are provided in the SoA. The PCRS will be administered prior to performing any efficacy assessments, followed first by the MADRS (SIGMA) and then by the HAM-A (SIGH-A).5.I.8.I. Montgomery-Asberg Depression Rating Scale (MADRS)

[0154] The MADRS is a validated 10-item questionnaire to assess depression severity and is commonly used to assess efficacy of an intervention in clinical trials. Each item of the MADRS is measured on a scale of 0 to 6 (for a total score of 0 to 60) with higher scores indicating more severe depression. The MADRS will be administered using a modified Structured Interview Guide for the MADRS and will be completed by the Central Rater. The standard administration and rating guidelines of the MADRS will be slightly modified to increase differentiation of symptoms related to depression versus illness. Specifically, Central Raters will be trained to ask more follow-up questions to make these differentiations. The Central Rater’s will be trained and certified on these modified administration and rating guidelines. The accepted definition of response is a reduction in total score of >50% from baseline at a given follow-up time point, while the accepted definition of remission is a MADRS score <10. The MADRS evaluation will be preceded by a standardized PCRS reminding participants to report their symptoms accurately at each timepoint in order to reduce potential “placebo” response.79 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0155] The past week version of MADRS will be administered in most instances. For visits where the visit window requires it, a modified ‘since last evaluation’ version of the assessment will be used.5.1.8.2. Hamilton Rating Scale for Anxiety (HAM-A)

[0156] The HAM-A is a 14-item scale that is used to rate the severity of symptoms of anxiety. Each of the 14 items is defined by a series of symptoms and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Items are scored from 0 (not present) to 4 (very severe), for a total score ranging from 0 to 56. Scores <17 indicate mild anxiety, scores of 8 to 14 indicate mild anxiety, 15-23 indicates moderate anxiety, and scores of 24 or higher indicates severe anxiety. A modified Structured Interview Guide for the Hamilton Anxiety Scale will be completed by the Central Rater. Participants will be reminded of the importance of reporting their symptoms accurately prior to completion of the HAM-A through use of the PCRS. The standard administration and rating guidelines of the HAM-A will be slightly modified to increase differentiation of symptoms related to anxiety versus illness. Specifically, Central Raters will be trained to ask more follow-up questions to make these differentiations. The Central Raters will be trained and certified on these modified administration and rating guidelines.5.1.8.3. Patient Global Impression-Change (PGI-C) and Patient Global Impression-Severity (PGI-S)

[0157] The Patient Global Impression Scale is the counterpart of the Clinical Global Impression Scale, adapted to the participant. It mainly measures change in clinical status (PGI-C) but can also measure disease severity (PGI-S). The PGI-C measures clinical status change according to the following parameters: much better, a little better, no change, a little worse, much worse. The PGI-S grades severity of symptoms according to the following parameters: none, mild, moderate, and severe. The 3 global measures rated include: AjD, Depression and Anxiety.5.1.8.4. Clinical Global Impression-Change (CGI-C) and Clinical Global Impression-Severity (CGI-S)

[0158] The Clinical Global Impression Scale is a clinician-rated instrument initially comprised of 3 global measures: severity of illness, global improvement, and efficacy index. The CGI-S grades severity of symptoms on a scale from 1 (normal, not ill at all) to 7 (among80 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) the most extremely ill patients). Over the years, CGI scales were used in a broad range of diseases and were modified for the purpose of clinical settings. The CGI-C is a measure of clinical change, with scores ranging from 1 (very much improved) to 7 (very much worse). The CGI assessments for this study will focus on the severity and change in AjD, anxiety and depression.5.1.8.5. Hospital Anxiety and Depression Scale (HADS)

[0159] The HADS is a self-report scale used to measure the severity of depression and anxiety in patients with comorbid medical conditions. The questionnaire comprises 14 items (7 for anxiety and 7 for depression), with a score ranging between 0 and 21 for the anxiety and depression subscales. Scores between 8 and 10 indicate a moderate presence of symptoms, whereas a score greater than 11 indicates a significant number of symptoms that likely correspond with a clinical diagnosis.5.1.8.6. Patient Health Questionnaire-9 (PHQ-9)

[0160] The PHQ-9 is a validated patient-rated questionnaire to screen for depression and also to diagnose and monitor the severity of the condition. The PHQ-9 consists of 9 questions that ask respondents how often they have “been bothered by any of the following problems” in the past 2 weeks. The questions address sleep, energy, appetite, and other possible symptoms of depression. Scores are calculated based on how frequently a person experiences these feelings.

[0161] Each “not at all” response is scored as 0; each “several days” response is 1; each “more than half the days” response is 2; and each “nearly every day” response is 3. The sum value of these responses provides the total score with a higher score indicating more severe depression.5.1.8.7. General Anxiety Disorder (GAD-7)

[0162] The GAD-7 is a self-report scale to screen, diagnose, and assess the severity of anxiety disorder, based on the generalized anxiety disorder diagnostic criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM). It is comprised by 7 items, with scores for individual items ranging from 0 (not at all) to 3 (nearly every day) for a possible total score ranging from 0 to 21, and higher scores indicating higher levels of anxiety symptoms.81 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1.8.8. Adjustment Disorder New Module 20 (ADNM-20)

[0163] The ADNM-20 is a self-report measure developed to measure emotional or behavioral reactions to an identifiable stressor. The stressor list captures a broad range of acute and chronic life events of the past 2 years. The item list measures the symptoms in response to the most distressing event(s). The ADNM-20 consists of 6 subscales: preoccupation (4 items), failure to adapt (4 items), avoidance (4 items), depressive mood (3 items), anxiety (2 items), and impulse disturbance (3 items). Participants indicate on a 4-point Likert scale, ranging from 1 (never) to 4 (often), how often they have experienced different symptoms during the past 2 weeks.5.1.8.9. Demoralization Scale Version II (DS-II)

[0164] The Demoralization Scale (DS) was initially developed and validated in 2004 to enable the measurement of demoralization in patients with advanced cancer. The DS-II is a 16-item revised questionnaire with 2 subscales (“Meaning and Purpose” and “Distress and Coping Ability”) demonstrate sound internal and external validity, making it a more practical measure of demoralization for research and clinical use.5.1.8.10. Patient-Reported Outcomes Measurement Information System - Short Form (PROMIS-SF)

[0165] The PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and social health, which can be used with the general population and with individuals living with chronic conditions. The original questionnaire contains more than 100 health-related QoL items, highlighting the importance of identifying a short list of domains that are relevant for most health contexts, leading to the development of several short forms of the original PROMIS.

[0166] Participants will be asked to complete the following PROMIS-SF measures at the timepoints indicated in the SoA:• PROMIS-SF v2.0 - Physical Function 4a• PROMIS-SF vl .0 - Fatigue 4a• PROMIS-SF vl.O - Sleep Disturbance 4a• PROMIS-SF v2.0 - Ability to Participate in Social Roles and Activities 4a• PROMIS-SF vl.O - Pain Interference 4a5.1.8.11. Placebo-Control Reminder Script (PCRS)82 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0167] The PCRS educates clinical trial participants of key causes of the placebo and nocebo effects, namely the tempering of participant study expectations, reminding subjects what a placebo is and how that relates to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differ from their experience with previous providers. To do this, the PCRS informs subjects that they are to be honest about their symptoms, site staff have no expectations of symptom improvement or worsening and will not be disappointed if they feel better, worse or the same, and asks participants to explain in their own words its content to ensure comprehension. Per the instructions on the PCRS, the efficacy scale rater will read the script verbatim immediately before administering efficacy scale. The PCRS is read to each subject at each visit (time point) as listed in the SoA, typically taking about 3 minutes to read. The PCRS has been empirically found to significantly manage (reduce) the placebo and nocebo effects.

[0168] In this study, the active control arm (low dose, 1.5 mg compound 1) is considered similar to a placebo in that it is being used to minimize the likelihood of functional unblinding of site staff and study participants.5.1.9. Other Assessments and Procedures5.1.9.1. Mini-Mental State Examination

[0169] The MMSE is a tool that can be used to systematically and thoroughly assess mental status. It is an 11 -question measure that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment. The MMSE takes 5-10 minutes to administer.5.1.9.2. Structured Clinical Interview for DSM-5 Axis I Disorders Clinical Trial Version (SCID-5-CT)

[0170] The Structured Clinical Interview for DSM-5 (SCID-5) is a semi -structured interview guide for making major DSM-5 diagnoses. The SCID-5 will be administered by the Clinical Site Rater. The SCID-5-CT is an adaptation that is reformatted and optimized for use in clinical trials that incorporate entry criteria relevant for a specific study.5.1.9.3. Mystical Experience Questionnaire 4-Item (MEQ-4)

[0171] The MEQ-4 is a shortened version of the MEQ-30, created to reduce the participant burden and potentially problematic patterns of response bias. The MEQ-4 uses the same 6- point scale as the MEQ-30, but with only with 4 items, each measuring one of the 4 subscales83 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)(i.e., Item 1 = “sense of oneness, insight into ultimate reality, or sacredness,” Item2 = “positive mood,” Item 3 = “transcendence of time and space,” and Item 4 = “ineffability [i.e., incapable of being expressed or described in words]”).

[0172] Participants will be asked to rate each item of the MEQ-4 on a 6-point scale.5.1.9.4. Blinding Assessment

[0173] The adequacy of the blind will be determined by asking the participant and all raters (Central Rater, Clinical Site Rater, including the Patient-Reported Outcomes Administrators) to assess which treatment the participant received, scored on a 5-point Likert scale:1. l am positive I / the participant received the higher dose of study drug.2. I think I / the participant received the higher dose of study drug.3. I cannot tell whether I / the participant received the higher dose of study drug.4. I think I / the participant received the lower dose of study drug.5. l am positive I / the participant received the lower dose of study drug.5.1.9.5. Session Support and Facilitation

[0159] During the conduct of this study, psychological support intended for patient safety will be provided during the pre-dose preparatory, dosing, and post-dose follow-up sessions by qualified and trained Session Monitors and in line with the Food and Drug Administration (FDA) Draft Guidelines on Psychedelic Drugs. The sessions are to be considered supportive, without formal or manualized psychotherapy. Session monitors will receive study-specific training that includes training on reporting adverse side effects, including AESI, that may occur during sessions, and the Session Monitor Manual, which provides detailed information about the conduct and content of the sessions. All sessions will be recorded.5.I.9.5.I. Pre-Dose Preparatory Sessions

[0160] After primary eligibility is confirmed, the participant will complete 2 preparatory sessions lasting approximately 60 minutes. The aim of the preparatory sessions is to prepare and educate participants about dosing and post-dosing experiences and their management, as applicable. During the preparatory sessions, the Session Monitor will inform participants about what to expect and how to respond to the potential acute compound 1 post-dose effects, common experiences and techniques used to provide psychological support during the dosing session, and to establish rapport and trust. Additional preparatory sessions may be conducted at the discretion of the Investigator or LSM.84 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)5.1.9.5.2. Dosing Sessions

[0161] The Dosing Session will be supported by the LSM and ASM for a minimum of 8 hours post-dose. Session Monitors will ensure psychological safety of participants, including the management, support and resolution of challenging experiences, throughout the dosing session using the procedures described in the study Session Monitor Manual.

[0162] At least 1 Session Monitor will be physically present with the patient at all times through 8 hours post-dose; if only 1 Session Monitor is physically present in the dosing room, the other must monitor the session on-site live via remote video monitoring. Site staff may also be in the dosing room at times to conduct assessments. If the LSM is not a physician, a licensed physician will be available or on-call and be able to reach the clinical site within 15 minutes in the event of a physiological or psychiatric emergency during dosing session.5.1.9.5.3. Post-Dose Follow-up Session

[0163] The LSM who attended the preparatory and dosing sessions will meet with the participant during 2 follow-up visits to help the participant review and integrate their experience and assess their mental health status as a part of the safety risk management. These sessions will also help to coordinate with the study team if any other assessments or follow-up may be needed. Additional post-dosing follow-up sessions may be conducted at the discretion of the Investigator.5.1.9.6. Discharge Readiness Assessment

[0164] The post-dose discharge readiness evaluation will be a clinical examination which will include an assessment of the participant’s psychiatric and physical status and associated health parameters including vital signs and status of any treatment-emergent AEs. Discharge readiness review will be performed between the 3 -hour and 8-hour post-dose timepoint.

[0165] The participant must not be discharged prior to 8-hours post-dose (regardless of prior documented “readiness”). If the participant’s clinical condition does not warrant discharge at the 8-hour post-dose timepoint, the participant will be managed under standard of care until ready for discharge and confirmed by a medically qualified Investigator.

[0166] At discharge, participants must be: (1) fully ambulatory with good balance; (2) have confirmed cardiovascular parameters, including stable vital signs, within normal limits or not clinically significantly elevated compared to baseline; and (3) be psychologically stable,85 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) oriented in time and space with no hallucinations (as assessed by BPRS+), and with no evidence of suicidality (as assessed by C-SSRS). In addition, all AEs, including any signs or symptoms of serotonin-related adverse reactions (such as shivering and tremors, twitching or involuntary movements, and / or sweating) must be resolved or stable and not clinically significant at time of discharge. This includes any residual effects from rescue medications administered, such as benzodiazepines (e.g., respiratory depression, excessive sedation, confusion, or balance difficulties).5.1.9.7. Entry and Exit Interviews

[0167] Approximately 30 to 40 semi -structured concept elicitation and cognitive debriefing entry interviews will be conducted remotely with randomly selected study participants with AjD representing participants from both cancer and other medical illness and each AjD specifier groups. The entry interviews will be conducted not only in participants who are deemed eligible for the study, but also in a subset of individuals who were deemed ineligible for the study (screen failures.

[0168] In addition, approximately 30 semi-structured concept elicitation exit interviews of randomly selected study participants, representing participants from both cancer and other medical illness and each AjD specifier groups, will be completed remotely once the participant has completed the end of study visit.

[0169] The goal will be to identify individuals and participants throughout the enrollment period of the study, such that entry and exit interviews are conducted both with participants who were recruited and screened early during the enrollment period, as well as those who were recruited later in the enrollment period. Utilizing a study-specific interview guide, third- party interviewers who are experienced health researchers skilled in qualitative research will conduct one-on-one interviews with the participant. These entry and exit interviews will take place via an online telehealth conference at the beginning of the study during the screening period and at the end of the study and will take approximately 60 minutes to complete. Each interview will be recorded and later transcribed to allow for qualitative analyses of the results. The entry and exit interview will contain questions on the participant’s experience of AjD, perspective on study assessments used to evaluate AjD during the study, and experience of the study treatment.

[0170] The entry interviews will be used to collect input regarding symptoms and impacts of AjD that are relevant and to cognitively debrief the PGI-S and PGI-C items. The exit86 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) interviews will be used to collect input regarding symptoms and impacts of AjD that are relevant and meaningful to participants to help support the definition of meaningful change thresholds. Any reported symptoms during the interview will be documented, and the site will be notified to assess if the report(s) should be recorded as AE(s).5.1.10 Safety Assessments

[0171] Planned timepoints for all safety assessments are provided in the SoA.5.1.10.1. Physical Examinations• A complete physical examination will be conducted at Screening and will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Height (cm) and weight (kg) will also be measured and recorded. Height should only be recorded at Screening.• Participants with ALS should be assessed for presence of fasciculations at Screening. Development of fasciculations or worsening of pre-existing fasciculations after dosing should be reported as an AE.• Brief physical examinations will be symptom-directed.• Investigators should pay special attention to clinical signs related to previous serious illnesses.

[0172] Clinically significant findings from physical examinations conducted at Screening or Baseline will be documented as medical history. Any clinically significant findings from physical examinations conducted post-dose will be recorded as an AE.5.1.10.2. Vital Signs• Temperature (°C), heart rate, and blood pressure will be recorded (before blood collection for laboratory tests).• Blood pressure and pulse measurements will be assessed with a completely automated device. Manual techniques will be used only if an automated device is not available.• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest (in the supine position) for the participant in a quiet setting without distractions (e.g., television, cell phones).• Vital signs will be measured after 5 minutes rest and will include temperature, systolic and diastolic blood pressure, and pulse.87 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)• Oxygen saturation and manually assessed respiratory rate will be measured at select visits as specified in the SoA.• For orthostatic blood pressure assessments (measured at Screening only), following measurement in a supine position, the participant will stand and blood pressure will be measured 1 minute and 3 minutes after standing.5.1.10.3. Pulmonary Function Testing (PFT)

[0173] PFT will only be performed for participants with ALS, IPF or a history of treatment for thoracic cancer or a history of surgical resection of lung cancer. PFT includes spirometry and DLCO.5.1.10.3.1. Spirometry

[0174] FVC and FEV1 will be assessed using standardized spirometry equipment according to the ATS / ERS guidelines. These assessments will be used to determine percent predicted FVC, percent predicted FEV1, and the FEV1 / FVC ratio.5.1.10.3.2. Diffusion Capacity for Carbon Monoxide (DLCO)

[0175] Single breath DLCO testing will be carried out according to the ATS / ERS guidelines. This assessment will be used to determine percent predicted DLCO.5.1.10.4. Electrocardiograms

[0176] Standard 12-lead ECGs will be recorded in the supine position, allowing 5 minutes of rest and before performing any venipuncture. ECGs will be reviewed for any clinically relevant abnormalities by a central reader, and categorized as normal, borderline (abnormal, not clinically significant), or abnormal (clinically significant). ECGs on Day 0, prior to dosing, will be evaluated locally by the investigator to confirm eligibility. Triplicate ECGs will be obtained at all timepoints on Day 0.

[0177] The following intervals or derivatives will be measured and captured in the database:• Heart rate (bpm)• PR-interval (ms)• QRS-interval (ms)• QT interval (ms)• QTc interval (using Fridericia’s formula)5.1.10.5. Clinical Safety Laboratory Tests88 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0178] The Investigator must review the laboratory results, document this review, and record any clinically significant changes occurring during the study as an AE. The laboratory results must be retained with source documents.

[0179] Abnormal laboratory findings associated with the underlying disease are not considered clinically significant unless judged by the Investigator to be more severe than expected for the participant’s condition.

[0180] All laboratory tests with values considered clinically significantly abnormal during participation in the study should be repeated until the values return to normal or baseline or are no longer considered clinically significant by the Investigator or Medical Monitor.

[0181] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples. If clinically significant values do not return to normal / baseline within a period of time judged reasonable by the Investigator, the etiology should be identified, and the Sponsor notified.

[0182] If laboratory values from non-protocol-specified laboratory tests performed at the institution’s local laboratory require a change in participant management or are considered clinically significant by the Investigator (e.g., SAE, AE, or dose modification), then the results must be recorded.5.1.10.6. Pregnancy Testing

[0183] For female participants, pregnancy testing will occur by assessment of serum betahuman chorionic gonadotropin at Screening and Day 42, and urine beta-human chorionic gonadotropin at Day 0 prior to dosing. For participants with a positive pregnancy test at Screening, 1 re-screen will be allowed.5.1.10.7. Suicidal Ideation and Behavior Risk Monitoring

[0184] Participants should be monitored appropriately and observed closely for suicidal ideation and behavior or any other unusual changes in behavior. Participants who experience signs of suicidal ideation or behavior should undergo a risk assessment.

[0185] When informed consent has been given, families and caregivers of participants being treated should be alerted about the need to monitor participants for the emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and behavior and to report such symptoms immediately to the study Investigator.89 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0186] Baseline assessment of suicidal ideation and behavior will be monitored using the C- SSRS. The “baseline / screening” version will be administered at Screening. From Visit 2 through the Follow-Up Period, the “since last visit” version will be administered.

[0187] The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item scale. The C-SSRS also captures information about the intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons for the most severe types of ideation. In addition, the C-SSRS captures information using yes / no questions and answers on suicidal behavior, specifically actual, interrupted, and aborted attempts; preparatory acts or behavior; and if suicidal behavior was present during the assessment period. For actual attempts only, the actual or potential lethality is classified for the initial, most lethal, and most recent attempts.5.1.10.8. Monitoring for Psychosis

[0188] Participants will be monitored for the presence of psychosis after the dosing session during the Follow-Up Period using the BPRS+. The BPRS+ is a 4-item subscale of the 18- item BPRS, used to assess symptoms of psychosis, anxiety, and depression. The 4-item positive symptom subscale assesses hallucinations, unusual thought content, suspiciousness, and conceptual disorganization, scored on a scale from 1 (not present) to 7 (extremely severe) with a score range of 4 to 28. A score of 0 is recorded if the symptom is not assessed.5.1.10.9. Adverse Events, Serious Adverse Events, and Other Safety Reporting

[0189] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug.

[0190] An AE or suspected adverse reaction is considered “serious” if, in the view of either the Investigator or Sponsor, it results in any of the following outcomes:• Death (death should be recorded as the outcome and the initiating event leading to death as the event)• Life-threatening (i.e., immediate risk of death from the event as it occurred; this does not include an AE that, had it occurred in a more serious form, might have caused death)90 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)• Persistent or significant disability / incapacitation• Inpatient hospitalization or prolongation of existing hospitalization• Congenital anomaly / birth defect

[0191] Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE reporting is appropriate in other situations such as significant medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should usually be considered serious.5.1.10.9.1. Time Period and Frequency for Collecting AE and SAE Information

[0192] All SAEs will be collected.

[0193] Medical occurrences that begin before the start of study drug but after obtaining informed consent will be recorded as medical history / current medical conditions, not as AEs unless associated with study procedures.

[0194] All SAEs will be 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.

[0195] Investigators are not obligated to actively seek information on AEs or SAEs after 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 the Investigator considers the event to be reasonably related to the study drug or study participation, the Investigator must promptly notify the Sponsor.5.1.10.9.2. Method of Detecting AEs and SAEs

[0196] Care will be 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.5.1.10.9.3. AE Detection and Assessment During the Dosing and Follow-up Sessions

[0197] AEs, including psychiatric AESIs that occur during the dosing session or are reported during follow-up sessions, will be documented by Session Monitors who are trained to record in source documents / progress notes the relevant data necessary to support AE reporting. The91 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) minimal information recorded by Session Monitors includes AE term, start and end date / time, severity, and any psychological, behavioral and pharmacological interventions, if applicable, with start and end time.

[0198] If the Session Monitor is not medically qualified, a study physician (per delegation) will be responsible for reviewing and discussing with the Session Monitor any relevant safety information documented in the session notes to report and record final AE information in the EDC (i.e., provide medical interpretation / confirmation of AE description / term, severity, relatedness). Session Monitors are trained not to discuss any other details that would cause unnecessary unblinding.5.1.10.9.4. Follow-up of AEs and SAEs

[0199] After the initial AE / SAE report, the Investigator is required to proactively follow each participant at subsequent visits / contacts. All AEs and SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up.5.1.10.9.5. Regulatory Reporting Requirements for SAEs

[0200] Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study drug under clinical investigation are met.

[0201] The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about certain safety events involving a study drug under clinical investigation. The Sponsor will comply with regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Boards (IRBs), and Investigators.

[0202] An Investigator who receives an Investigator safety report describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file it along with the Investigator’s Brochure and will notify the IRB, if appropriate according to local requirements.

[0203] Investigator safety reports must be prepared for SUSARs according to local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.5.1.10.10. Pregnancy

[0204] If a participant, or their partner, becomes pregnant during the study, the Investigator will notify the Sponsor or designated representative immediately after the pregnancy is confirmed.92 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0205] The Investigator will report any pregnancies using the eCRF Pregnancy Reporting Form within 24 hours of becoming aware of the event. The Investigator will also (1) notify the participant’s physician of the trial intervention they received, and (2) follow the progress of the pregnancy and document the outcome of the pregnancy. Pregnancy outcome information should be forwarded to the Sponsor or designated representative when available.

[0206] Details of all pregnancies in participants or their partners will be collected after the start of study drug and until the end of the Follow-Up Period (Day 42 / End of Study).

[0207] While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. The Investigator will report any pregnancies using the electronic case report form (eCRF) Pregnancy Reporting Form within 24 hours of becoming aware of the event.

[0208] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.

[0209] The participant or their pregnant partner will be followed (after providing informed consent regarding the collection of pregnancy information) to determine the outcome of the pregnancy. The Investigator will collect follow-up information on the pregnant participant or pregnant partner and the neonate, and the information will be forwarded to the Sponsor.

[0210] Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the Investigator will be reported.5.1.10.11. Assessment of Injection Site Reactions

[0211] Following administration of study drug, the location of the SC injection will be evaluated to determine if there were any local changes to the area surrounding the injection site per the SoA. If findings are observed, a detailed description of the events should be included in the source documentation and appropriate AE term included in the case report form.5.1.10.12. Adverse Events of Special Interest

[0212] An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and medical concern specific to study medication, for which ongoing monitoring and timely notification by the Investigator to the Sponsor is required. Such AESIs may require further investigation to characterize and understand them. Investigators are instructed to inquire about the occurrence of such events during the collection of AEs at each visit.93 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)When reported, the Investigator will be required to obtain detailed information of the event and its clinical course including information regarding time of onset and duration of the event, severity and outcome (recovered, resolving, or ongoing).

[0213] Note that if the event meets the seriousness criteria, the Serious Adverse Events Form must also be completed according to the SAE reporting timeline, i.e., within 24 hours of having become aware of the event, even if all details are not available.5.1.10.12.1. Psychiatric Adverse Events of Special Interest

[0214] AEs indicative of psychiatric AESIs (or which may be indicative of abuse potential) require prompt reporting in the eCRF regardless of relationship to study drug.

[0215] Investigators are responsible for ongoing monitoring and observation of suicidal ideation and behavior or any other unusual changes in behavior, including psychosis, that meet the criteria of AESIs. Investigators are expected to review or discuss C-SSRS and BPRS+ findings at each visit to ensure timely reporting of suicidal ideation or behavior that is not captured elsewhere.5.1.10.12.2. Seizure-related Adverse Events of Special Interest

[0216] Potential seizure-related activity is also considered an AESI and requires expedited reporting to Worldwide Clinical Drug Safety within 24 hours of becoming aware of the event. Seizure-related AESIs will subsequently be reported to the DSMB for further evaluation5.1.10.12.3. Adverse Events of Special Interest Related With Escalation of Care

[0217] Events related to post-dose escalation of care on the day of dosing, are considered AESIs and require prompt reporting in the eCRF.5.1.11. RESULTS

[0218] A single SC dose of 30 mg of compound 1 is effective to reduce depressive symptoms of AjD, as measured by change from baseline at Day 7 or Day 14 in MADRS total score.

[0219] A single SC dose of 30 mg of compound 1 is effective to reduce anxiety symptoms of AjD, as measured by change from baseline at Day 7 or Day 14 in Hamilton Rating Score for Anxiety (HAM- A).94 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0220] A single SC dose of 30 mg of compound 1 is effective to reduce symptoms of AjD, as measured by change from baseline at Day 7 or Day 14 in Hospital Anxiety and Depression (HADS) score.

[0221] A single SC dose of 30 mg of compound 1 is effective to reduce symptoms of adjustment disorder in the enrolled patients at Day 7 or Day 14, as measured by improvement in at least one of the following tests: Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Anxiety (HAM- A), Patient Global Impression-Change (PGI-C), Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Change (CGI-C), Clinical Global Impression-Severity (CGI-S), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder (GAD-7), Adjustment Disorder New Module 20 (ADNM-20), Demoralization Scale Version II (DS-II), and Patient-Reported Outcomes Measurement Information System - Short Form (PROMIS- SF).

[0222] A single SC dose of 30 mg of compound 1 is effective to reduce symptoms of adjustment disorder in the enrolled patients at Day 7 or Day 14, as measured by improvement in at least two of the following tests: Montgomery- Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Anxiety (HAM- A), Patient Global Impression-Change (PGI-C), Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Change (CGI-C), Clinical Global Impression-Severity (CGI-S), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder (GAD-7), Adjustment Disorder New Module 20 (ADNM-20), Demoralization Scale Version II (DS-II), and Patient-Reported Outcomes Measurement Information System - Short Form (PROMIS- SF).

[0223] A single SC dose of 30 mg of compound 1 is effective to reduce symptoms of adjustment disorder in the enrolled patients at Day 7 or Day 14, as measured by improvement in at least three of the following tests: Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Anxiety (HAM- A), Patient Global Impression-Change (PGI-C), Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Change (CGI-C), Clinical Global Impression-Severity (CGI-S), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder (GAD-7), Adjustment Disorder New Module 20 (ADNM-20), Demoralization Scale Version II (DS-II), and Patient-Reported Outcomes Measurement Information System - Short Form (PROMIS- SF).95 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)

[0224] A single SC dose of 30 mg of compound 1 is effective to reduce adjustment disorder in the enrolled patients with cancer at Day 7 or Day 14. A single SC dose of 30 mg of compound 1 is effective to reduce adjustment disorder in the enrolled patients with ALS. A single SC dose of 30 mg of compound 1 is effective to reduce adjustment disorder in the enrolled patients with MS. A single SC dose of 30 mg of compound 1 is effective to reduce adjustment disorder in the enrolled patients with Parkinson’s Disease (PD). A single SC dose of 30 mg of compound 1 is effective to reduce adjustment disorder in the enrolled patients with idiopathic pulmonary fibrosis (IPF).6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0213] While aspects of this disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the scope of the disclosure.

[0214] All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.96 of 1044925-5827-3149.1

Claims

Attorney Docket No.: 145737-0182 (008WO)WHAT IS CLAIMED IS:

1. A method of treating adjustment disorder (AjD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, wherein the compound is represented by:or is a pharmaceutically acceptable salt or zwitterion thereof.

2. The method of claim 1, wherein the adjustment disorder is associated with a primary disease or disorder.

3. The method of claim 2, wherein the primary disease or disorder selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), idiopathic pulmonary fibrosis (IPF), and cancer.

4. The method of claim 3, wherein the primary disease or disorder is cancer.

5. The method of claim 3, wherein the primary disease or disorder is ALS.

6. The method of claim 3, wherein the primary disease or disorder is MS.

7. The method of claim 3, wherein the primary disease or disorder is PD.

8. The method of claim 3, wherein the primary disease or disorder is IPF.

9. The method of any one of claims 1-8, wherein the compound is administered to the subject via subcutaneous injection.

10. The method of any one of claims 1-9, wherein a dose comprising from 0.1 mg to 100 mg of the compound is administered to the subject.

11. The method of claim 10, wherein a dose comprising from 25 to 75 mg of the compound is administered to the subject.

12. The method of claim 10, wherein a dose comprising 30 mg of the compound is administered to the subject.97 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)13. The method of any one of claims 1-12, wherein the compound is administered to the subject in the form of a liquid pharmaceutical composition, such as a solution.

14. The method of claim 13, wherein the liquid pharmaceutical composition comprises a pharmaceutically acceptable diluent.

15. The method of claim 14, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination thereof.

16. The method of claim 14, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

17. The method of claim 15 or 16, wherein the sodium phosphate dibasic is from 1 to 100 mM, such as 60 mM.

18. The method of claim 15 or 16, wherein the sodium chloride is from 1 to 100 mM, such as 40 mM.

19. The method of any one of claims 13-18, wherein the liquid pharmaceutical composition comprises a single fixed dose.

20. The method of any one of claims 1-19, wherein the compound is a zwitterion of compound 1.

21. The method of any one of claims 13-20, wherein the liquid pharmaceutical composition comprises (a) from 25 mg to 50 mg of a zwitterion of compound 1, e.g., from 25 mg to 35 mg, and (b) a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride, e.g., 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

22. The method of any one of claims 13-20, wherein the liquid pharmaceutical composition comprises (a) 30 mg of a zwitterion of compound 1 and (b) a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.

23. The method of any one of claims 1-22, wherein the subject exhibits improvement of one or more depressive symptoms following treatment.

24. The method of claim 23, wherein the depressive symptom is selected from lack of energy, difficulty sleeping, oversleeping, changes in appetite, unplanned weight98 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO) changes, headaches, cramps, difficulty concentrating, suicidal ideation, and depressive mood.

25. The method of claim 23, wherein improvement of one or more depressive symptoms is determined by a decrease in the subject’s Montgomery -Asberg Depression Rating Scale (MADRS) score following treatment compared to a baseline MADRS score measured prior to treatment.

26. The method of claim 25, wherein the subject exhibits at least a 20% decrease in MADRS score following treatment compared to the baseline MADRS score measured prior to treatment, or at least a 50% decrease in MADRS score following treatment compared to baseline.

27. The method of claim 25 or 26, wherein the subject’s MADRS score is measured at least 7 days after administration of the compound.

28. The method of any one of claims 1-27, wherein the subject exhibits improvement of one or more anxiety symptoms following treatment.

29. The method of claim 28, wherein the anxiety symptom is selected from restlessness, irritability, difficulty concentrating, fear, rapid heartbeat, sweating, trembling, nausea, dizziness, difficulty sleeping, feeling tired, and shortness of breath.

30. The method of claim 28, wherein improvement of one or more anxiety symptoms is determined by a decrease in the subject’s Hamilton Rating Score for Anxiety (HAM- A) score following treatment compared to a baseline HAM-A score measured prior to treatment.

31. The method of claim 30, wherein the subject exhibits at least a 20% decrease in HAM-A score following treatment compared to a baseline HAM-A score measured prior to treatment.

32. The method of claim 30 or 31, wherein the subject’s HAM-A score is measured at least 7 days after administration of the compound.

33. The method of any one of claims 1-32, wherein the subject exhibits a change in Hospital Anxiety and Depression Scale (HADS) following treatment compared to a baseline HADS score measured prior to treatment.99 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)34. The method of any one of claims 1-33, wherein the subject exhibits a change in the Patient Health Questionnaire (PHQ-9) following treatment compared to a baseline PHQ-9 score measured prior to treatment.

35. The method of any one of claims 1-34, wherein the subject exhibits a change in Generalized Anxiety Disorder 7-item (GAD-7) total score following treatment compared to a baseline GAD-7 total score measured prior to treatment.

36. The method of any one of claims 1-35, wherein the subject exhibits a change in Adjustment Disorder Module 20 (ADNM-20) following treatment compared to a baseline ADNM-20 measured prior to treatment.

37. The method of any one of claims 1-36, wherein the subject exhibits an improvement of demoralization, general health status, pain, quality of life, or a combination thereof following treatment.

38. The method of claim 37, wherein the subject’s improvement is determined by a change in one or more of the following; a. Demoralization Scale Version II (DS-II) following treatment compared to a baseline DS-II measured prior to treatment; b. Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form (SF) v2.0-Physical Function 4a score following treatment compared to a baseline PROMIS-SF v2.0 Physical Function 4a score measured prior to treatment; c. PROMIS-SF vl .0-Sleep Disturbance 4a score following treatment compared to a baseline PROMIS-SF vl.O-Sleep Disturbance 4a score measured prior to treatment; d. PROMIS-SF v2.0-Fatigue 4a score following treatment compared to a baseline PROMIS-SF v2.0-Fatigue 4a score measured prior to treatment; e. PROMIS-SF v2.0-Ability to Participate in Social Roles and Activities 4a score compared to a baseline PROMIS-SF v2.0-Ability to Participate in Social Roles and Activities 4a score measured prior to treatment; and f. PROMIS-SF vl .0-Pain Interference 4a score compared to a baseline PROMIS-SF vl.0-Pain Interference 4a score measured prior to treatment.100 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)39. The method of any one of claims 1-22, wherein the subject receives concomitant treatment with a selective serotonin reuptake inhibitor (SSRI).

40. The method of any one of claims 1-22, wherein the subject does not receive concomitant treatment with a SSRI.

41. The method of any one of claims 1-22, wherein, the subject receives concomitant treatment with psychotherapy.

42. The method of any one of claims 1-22, wherein the subject does not receive concomitant treatment with psychotherapy.

43. The method of any one of claims 1-22, wherein prior to administration of the compound, the subject meets DSM-5-TR diagnostic criteria for AjD.

44. The method of claim 43, wherein the subject meets the DSM-5-TR diagnostic criteria for AjD for at least 4 weeks prior to administration of the compound.

45. The method of claim 43 or 44, wherein the subject has five or more symptoms of major depressive disorder (MDD) and / or major depressive episode (MDE) prior to administration of the compound.

46. A liquid pharmaceutical composition comprising a zwitterion of compound 1 and a pharmaceutically acceptable diluent.

47. The liquid pharmaceutical composition of claim 46, wherein the composition comprises from 0.1 mg to 100 mg of the zwitterion of compound 1, such as 25 mg to 35 mg, preferably 30 mg.

48. The liquid pharmaceutical composition of claim 46 or 47, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination thereof.

49. The liquid pharmaceutical composition of claim 46 or 47, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

50. The liquid pharmaceutical composition of claim 48 or 49, wherein the sodium phosphate dibasic is from 1 to 100 mM, such as 60 mM.

51. The liquid pharmaceutical composition of claim 48 or 40, wherein the sodium chloride is from 1 to 100 mM, such as 40 mM.101 of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)52. The liquid pharmaceutical composition of claim 49, wherein the sodium phosphate dibasic is from 1 to 100 mM, such as 60 mM; and the sodium chloride is from 1 to 100 mM, such as 40 mM.

53. The liquid pharmaceutical composition of any one of claims 46-52, wherein the liquid pharmaceutical composition comprises a single fixed dose.

54. A kit comprising: a. a first composition comprising a pharmaceutically acceptable salt of compound 1 in solid form; and b. a second composition comprising a pharmaceutically acceptable diluent.

55. The kit of claim 54, wherein the pharmaceutically acceptable salt of compound 1 is the hydrochloride salt.

56. The kit of claim 54 or 55, wherein the first composition comprises from 0.1 mg to 100 mg of the pharmaceutically acceptable salt of compound 1, such as 30 mg to 40 mg, or 36 mg.

57. The kit of any one of claims 54-56, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic, sodium chloride, or a combination thereof.

58. The kit of any one of claims 54-56, wherein the pharmaceutically acceptable diluent comprises an aqueous solution comprising sodium phosphate dibasic and sodium chloride.

59. The kit of claim 57 or 58, wherein the sodium phosphate dibasic is from 1 to 100 mM, such as 60 mM.

60. The kit of claim 57 or 58, wherein the sodium chloride is from 1 to 100 mM, such as 40 mM.

61. The kit of claim 57 or 58, wherein the sodium phosphate dibasic is from 1 to 100 mM, such as 60 mM; and the sodium chloride is from 1 to 100 mM, such as 40 mM.

62. The kit of claim 54, wherein the first composition comprises 30 mg to 40 mg of the hydrochloride salt of compound 1 and the second composition comprises a pharmaceutically acceptable diluent comprising sodium phosphate dibasic and sodium chloride.102 Of 1044925-5827-3149.1Attorney Docket No.: 145737-0182 (008WO)63. The kit of claim 54, wherein the first composition comprises 36 mg of the hydrochloride salt of compound 1 and the second composition comprises a pharmaceutically acceptable diluent comprising 60 mM sodium phosphate dibasic and 40 mM sodium chloride.103 of 1044925-5827-3149.1

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