Methods of using tryptamine prodrugs

Abstract

The present disclosure relates to methods of treating a psychological disease or disorder in a subject, such as postpartum depression, with conjoint administration of isoprocin-4- glutarate, or a pharmaceutically acceptable salt or zwitterion thereof, and a second therapeutic agent. The present disclosure also relates to methods of treating a psychological disease or disorder in a subject already on a stable regimen of antidepressants or established psychotherapy by administration of isoprocin-4-glutarate or a pharmaceutically acceptable salt or zwitterion thereof.

Description

Attorney Ref: 145737-0191 (007WO2)METHODS OF USING TRYPTAMINE PRODRUGS1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 777,549, filed March 25, 2025, and to International Application No. PCT / US2025 / 021388, filed March 25, 2025, the entire contents of each of which are incorporated by reference herein.2. BACKGROUND

[0002] In the Diagnostic and Statistical Manual of Mental Disorders, 5thEdition (DSM-5), postpartum depression (PPD) is diagnosed when a patient has a major depressive episode along with a peripartum-onset. The diagnostic criteria are the same as major depressive disorder with the additional requirement of symptom onset during pregnancy and up to 4 weeks following delivery. Five or more of the following symptoms must be present for ≥ 2 weeks with a change from previous functioning that causes clinically significant distress:1. Depressed mood (subjective or observed) present most of the day2. Loss of interest or pleasure, most of the day3. Insomnia or hypersomnia4. Psychomotor retardation or agitation5. Feelings of worthlessness or guilt6. Loss of energy or fatigue7. Suicidal ideation or attempt and recurrent thoughts of death8. Impaired concentration or indecisiveness9. Change in weight or appetite (weight change 5% over 1 month)

[0003] Additional symptoms associated with PPD include irritability, mood lability, anxiety, thoughts of harming the child, and obsessional worries or preoccupations with baby.

[0004] The worldwide incidence and prevalence of PPD is approximately 12% and 17%, respectively. Risk factors for PPD include history of depression and anxiety, complicated1 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)pregnancy including emergency cesarean section, lack of social support, and lifestyle choices (eating habits, sleep cycle, physical activities, and exercise).

[0005] As with other depressive disorders, PPD has a risk of suicidality and an increased prevalence of suicidal ideation and is therefore considered a life-threatening condition. In addition to the negative impact on maternal mental health, it is recognized that PPD can also have profound negative effects on the maternal-infant bond and later infant development, including impaired infant neurodevelopment and attachment, problems in cognitive, social, emotional, or physical development later in life, and an increased risk of developing depression during adulthood.

[0006] In patients with moderate or severe PPD, the current standard of care includes selective serotonin reuptake inhibitors (SSRIs) alone or with psychological treatment, despite lack of regulatory approval of SSRIs specifically for this indication and associated poor response and unwanted side effects. In 2019, Zulresso® (brexanolone) became the first United States Food and Drug Administration approved treatment for PPD and was indicated for the treatment of moderate to severe PPD. Brexanolone was to be administered as a single dose intravenous (IV) infusion requiring several dose titration steps over a continuous infusion period of 60 hours and had a boxed warning for excessive sedation and sudden loss of consciousness, requiring continuous monitoring. While brexanolone provided a rapid response with a decrease in depressive symptoms in patients with moderate to severe PPD documented 24 hours postinfusion, it was only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Along with the high cost of treatment, these restrictions presented a significant barrier to its access and wide-spread use, and Zulresso® was discontinued from commercialization in 2024.

[0007] Zurzuvae® (zuranolone) was approved for the treatment of PPD in 2023. Zuranolone is an oral medication administered daily over a 2-week period. However, zuranolone also has a boxed warning, related to central nervous system depressant effects, and is available only through a restricted REMS program. Furthermore, zuranolone has been shown to impair simulated driving and to reduce cognitive function when assessed 9 hours post-dose. While cognitive impairment resolved 7 days after dosing, driving remained impaired.2 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0008] Psychedelic substances have been shown to be effective for treating depression.Psilocybin is a naturally occurring plant-based tryptamine found in Psilocybe mushrooms, and produces a prolonged psychedelic state of about 6 to 8 hours. Psilocybin was first synthesized in 1958 and is currently being investigated as a treatment for depression. Psilocybin is a prodrug, with psilocin being the active species in vivo. Psilocybin contains a phosphate bound to the 4-hydroxy group of psilocin, which is cleaved in the gut when Psilocybe mushrooms or the drug substance is taken orally:Psilocybin Psilocin

[0009] 4-Glutaroyl-3-[2-diisopropylaminoethyl]-1H-indole (compound 1) is a prodrug of the synthetic psychedelic drug 3-(2-diisopropylaminoethyl)-1H-indol-4-ol (also called 4-OH-DiPT), a molecule structurally related to psilocin, the active metabolite of psilocybin. Compound 1 converts to the pharmacologically active 4-OH-DiPT in vivo by hydrolysis of a glutaric acid group.

[0010] The active molecule, 4-OH-DiPT, is a serotonin (5-HT) agonist, notably on 5-HT2A. Activation of this receptor is proposed to contribute to 4-OH-DiPT mediated activity, based on the mechanisms described for psilocybin. The most important of these receptors is the 5-HT2A receptor which is suggested to account for its psychedelic activity. In compound 1, shown below as the hydrochloride salt, a glutaric acid group at the 4-position of the tryptamine hydrolyzes to form 4-OH-DiPT, which is responsible for the agonist activity at 5-HT2A:3 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 HCl 4-OH-DiPT Psilocin (4-OH-DMT)

[0011] Classic serotonergic hallucinogenic drugs, a group of compounds which bind to 5-hydroxytryptamine (5-HT) receptors, are characterized by their capability to induce changes in sensory perception, emotion, thought, and sense of self, leading to remodeling in mental functions (Vollenweider, 2001; Kometer et al, 2012; Vollenweider et al., 1998) and referred to as mystical-type experiences occurring during psilocybin treatment. These changes have been repeatedly observed to predict subsequent effects on behavior and emotions, including reductions in depressive and anxious behavior (Griffiths et al., 2011; Griffiths et al., 2016; Ross et al., 2016).

[0012] Several lines of evidence suggested that serotonergic hallucinogens, such as psilocin and 4-OH-DiPT, have clinical potential for inducing therapeutically beneficial behavior changes in a variety of psychiatric conditions. Enduring changes in attitudes, depression, anxiety, wellbeing, substance misuse, and mindfulness have been documented after administration of a psychedelic. Mystical experiences, connectedness, emotional breakthrough and increased neural entropy are related to these long-term changes in psychological functioning (Aday et al., 2020). Additionally, there is emerging evidence that psychedelic-assisted psychotherapy can be a potent treatment for depression and other psychological disorders (Carhart-Harris et al., 2016).

[0013] WO 2024 / 145719 describes a Phase 1 clinical trial of a single subcutaneous dose escalation trial using compound 1 in healthy women. Compound 1 was generally well tolerated with robust pharmacodynamic (PD) effects observed at doses >30 mg that closely aligned with the pharmacokinetic (PK) profile of 4-OH-DiPT. The adverse effect (AE) profile of compound 1 was determined to be similar to psilocybin (Goodwin et al.; and Carbonaro et al.) with no serious AEs and no clinically significant vital sign, clinical laboratory, or electrocardiogram findings at doses up to and including 44 mg. The therapeutically relevant dose level (30 mg) confirmed that4 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)the overall safety profile of compound 1 appears to be consistent with those reported for other 5-HT agonists, including psilocybin and TEAEs observed are likely related to its mechanism of action, with a faster absorption and earlier peak activity (approximately 1 hour), and shorter duration of psychoactivity (the mean experience duration, based on a modified DEQ response score of > 3, ranged from 2.7 to 4.2 hours with doses > 30 mg.). During this trial, use of any psychotropic medications including SSRIs was prohibited.

[0014] There remains an unmet need for additional treatment options for patients with PPD, particularly for therapies that safely induce rapid symptom remission and improve quality of life, leading to improved maternal care, quality of the mother-infant interaction, and earlier return to routine activities and responsibilities.3. SUMMARY

[0015] In one aspect, the present disclosure provides a method for treating a psychological disease or disorder (e.g., PPD) in a subject in need thereof, the method comprising conjointly administering to the subject a therapeutically effective amount of compound 1, wherein compound 1 is represented by:or is a zwitterion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant).

[0016] In another aspect, the present disclosure provides a method of treating a psychological disease or disorder (e.g., PPD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of compound 1 wherein the subject (a) has been on a stable regimen of a SSRI for at least 30 days prior to administration of compound 1 or (b) has been on established psychotherapy for at least 30 days prior to administration of compound 1.5 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0017] The methods of the present disclosure contemplate administering an acute dose of compound 1 to a subject already receiving therapy for depression (e.g., PPD), e.g., via a stable antidepressant regimen (e.g., a SSRI) or established psychotherapy. In certain embodiments, conjoint therapy provides synergistic action between compound 1 and antidepressant such that the subject’s depression (e.g., PPD) is treated more effectively than use of either compound 1 alone or the antidepressant alone.

[0018] In certain embodiments, the methods of the present disclosure effectively treat depression, major depressive disorder (MDD), PPD, or drug-resistant depression. In certain embodiments, the methods of the present disclosure effectively treat PPD.

[0019] In certain embodiments, the methods of the present disclosure effectively reduce depressive symptoms in the subject. In certain embodiments, the methods of the present disclosure effectively reduce anxiety symptoms in the subject. In certain embodiments, the methods of the present disclosure improve maternal behaviors in the subject.

[0020] In another aspect, the present disclosure provides use of a therapeutically effective amount of compound 1 and a therapeutically effective amount of a second therapeutic agent (e g., an antidepressant) for manufacturing a medicament for treating a psychological disease or disorder (e.g., PPD).

[0021] In another aspect, the present disclosure provides use of a therapeutically effective amount of compound 1 and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant) for treating a psychological disease or disorder (e.g., PPD).4. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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:

[0023] FIG. 1 shows a scheme of the clinical trial described in Example 1.

[0024] FIGs. 2A-2B show the Schedule of Activities (SoA) for the clinical trial described in Example 1. With respect to the SoA shown in FIGs. 2A-2B:6 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)a' VI and V2 assessments may be performed over multiple days within the protocol defined visit windows.bEligibility review process with Study Medical Monitor and Study Central CAT Reviewer will be performed prior to randomization to confirm eligibility. In the event that additional time during the screening period is required to facilitate eligibility review (i.e., unanticipated delays in obtaining necessary / requested medical records) an extension of the screening period up to 7 additional days may be approved by the Sponsor on a case-by-case basis.cDate of last menstrual period from time of consent through last study visit must be recorded.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.eHeight will only be measured and recorded at Screening.fClinical safety laboratory evaluations will include hematology, serum chemistry, coagulation, and select hormone parameters. The urine test will include a urinalysis (specific gravity; pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick; microscopic examination [if blood or protein is abnormal]). Serology will be performed at Screening only and will include HIV antibody, HbsAg, and hepatitis C virus antibody.gUrine for selected drugs of abuse and breathalyzer for alcohol.hPatients will be provided with a COVID-19 antigen test kit at Screening (Visit 1) for selfadministration and reporting to site staff at Baseline (Visit 2) to support the eligibility requirement of a negative antigen test within 14 days prior to Day 0 (Baseline).iVital signs will include temporal temperature, heart rate, and blood pressure in the supine position after 5 minutes of rest. On dosing day (Day 0), vitals are to be assessed pre-dose, 1-, 3-, 4-, 5-, 6-, 7-, and 8-hours post-dose.j ECGs will be recorded in the supine position, allowing 5 minutes of rest, and before performing any venipuncture. On dosing day (Day 0), ECGs are to be assessed pre-dose, 1-, 4-, 5- 6-, and 8-hours post-dose. Triplicate ECGs will be obtained at all Day 0 timepoints.kThe C-SSRS “baseline / screening” version will be administered at Screening and Day -1, while the C-SSRS “since last visit” version will be administered thereafter.lThe PCRS is to be administered to each subject immediately before administering any efficacy assessment as indicated in the table (i.e., prior to the HAMD-17 at Screening and Day -1; and MADRS at Days 0, 1, 7, 14 and 28).mThe MADRS and HAM-A will be performed by a qualified blinded independent rater using the SIGMA and SIGH-A (respectively) and confirmed through a review by an independent centralized reviewer. The MADRS should be done prior to any other efficacy assessments. *For the Day 1 assessment only, the 24-hour recall version of the MADRS (MADRS-24hr) was used; all other MADRS assessments will use the standard 1-week (7-day) recall version.nThe MEQ-4 and CEQ-7 should be administered after the dosing session prior to discharge.0Patient will be monitored by the 2 Session Monitors from study drug administration until effects of dosing have resolved (through at least 8 hours post-dose).pAssessments will be conducted hourly between 4-hour and 8-hour post-dose timepoints inclusive. Discharge may only occur at the 8-hour post-dose timepoint (or thereafter per 7 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)investigator judgement, if patient is not ready for discharge at 8-hour timepoint). C-SSRS and BPRS+ will be completed only once at the 8-hour timepoint.qRemote check-in will occur a few hours post discharge at the time agreed upon with the patient.rIntegration session will occur after clinical ratings are completed. The second integration session may be done in person or remotely at Day 7 (± 2 days). Additional integration sessions may be conducted at the discretion of the Investigator. Refer to the Session Monitor’s Manual for guidelines for each session.sAE assessment includes assessment of injection site reactions, to be done prior to discharge and during follow-up.tRemote assessment will include assessments of AEs and patient risk for suicide and suicidal behavior using the C-SSRS via interview by a qualified investigator.uIncludes prior use of hallucinogenic agents.

[0025] FIG.3 is a flow chart showing the disposition of the participants in the study described in Example 1. With respect to FIG.3:a- Percentages are based on the number of early withdrawals by treatment group.bPercentages are based on the number of participants in the Randomized Set by treatment group.

[0026] FIG. 4A is a line-plot of mean (± standard error) MADRS total score over time for the Full Analysis Set (all randomized participants who received study drug and had a valid Baseline MADRS assessment).

[0027] FIG. 4B is a plot of the least square mean (± standard error) of change from baseline in MADRS total score over time for the Full Analysis Set. Missing data due to withdrawal because of lack of efficacy was imputed 1000 times under Missing Not at Random (MNAR) whereas all remaining missing data were imputed under a Missing at Random (MAR) mechanism. The mixed model for repeated measures (MMRM) includes treatment, visit, treatment by visit interaction, Baseline MADRS total score and an unstructured correlation matrix. The imputed datasets were analyzed using the MMRM model and estimates pooled using Rubin’s rules.

[0028] FIGs. 5A-5B show a forest plot of mean (± 90% Confidence Intervals) change from baseline of MADRS total score at Day 7, by subgroup (Abbreviations: CI = Confidence Interval; MADRS = Montgomery-Asberg Depression Rating Scale; SSRI = selective serotonin reuptake8 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)inhibitors; PPD = postpartum depression). Participants were classified in the 'Incorrect Lookback' stratum if, on at least 1 occasion, the wrong lookback period was used.5. DETAILED DESCRIPTION

[0029] As described herein, the present inventors determined that subcutaneous administration of compound 1 provides a rapid and sustained antidepressive activity along with improvements in symptoms related to mood and anxiety disorders as early as one day after administration, with significant improvement observed by Day 7 and sustained benefit maintained for at least 28 days. Additionally, compound 1 is effective in treating patients with several months of disease duration and patients receiving concurrent antidepressant or psychotherapeutic treatment.5.1. Definitions

[0030] 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.

[0031] 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 limited 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 9 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)least the recited number (e., 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.”

[0032] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0033] 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 easily 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.10 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0034] As used herein, “conjointly administering” refers to any form of administration of two or more different therapeutic compounds such that the second administered compound is administered while the first administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include additive or synergistic effects of the two compounds). For example, compound 1 and a SSRI can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of the different therapeutic compounds.

[0035] As used herein, the term “effective amount,” means a sufficient amount of the therapeutic agent or composition to provide the desired utility when administered to a subject. The term “effective amount” therefore refers to an amount of a therapeutic agent or composition that is sufficient to promote a particular effect when administered to a subject in need of treatment. In certain embodiments, an effective amount includes an amount of therapeutic agent or composition sufficient to prevent or delay the development of a symptom of the disease, alter the course of a symptom of the disease (for example but not limited to, slow the progression of a symptom of the disease), or reverse a symptom of the disease. It is understood that for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using routine experimentation. For example, when administered in clinic, such therapeutic agent or compositions will contain an amount of active ingredient effective to achieve the desired result.

[0036] As used herein, the term “established psychotherapy” refers to a psychotherapy regimen that has been stable in terms of frequency for a given timeframe (e.g., at least 30 days).

[0037] As used herein, the term “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. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid11 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenyl propionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N (Ci 4alkyl >4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0038] As used herein, “subject” refers to the person or organism to which the therapeutic agent or 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, baboons, 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.

[0039] As used herein, a “stable regimen” refers to a subject’s maintenance dosing regimen for a particular drug (e.g., a SSRI) that has remained constant throughout a particular timeframe (e.g., 30 days) and wherein the dose and timing of administration of the drug has already been optimized for treating the subject’s disorder. A “stable regimen” does not include the induction or optimization phases wherein the dose or timing of administration of the drug is altered by a medical provider seeking to achieve improved results in the subject.

[0040] As used herein, “treating” or “treatment” have the broadest meaning commonly accepted in the art of psychological disease or disorder, and therefore do not require cure or remission.12 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)The terms include, for example, a suppression or an amelioration of the symptoms associated with the disorder afflicting the subject, where suppression and amelioration are used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the disorder being treated. As such, treatment also includes situations where the disorder is completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the subject no longer experiences the disorder. As such, treatment includes both preventing and managing a disorder.

[0041] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In certain embodiments, the present disclosure includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein.

[0042] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.5.2. Methods

[0043] In one aspect, the present disclosure provides a method of treating a psychological disease or disorder (e.g., postpartum depression) in a subject in need thereof. In some embodiments, the method comprises conjointly administering to the subject a therapeutically effective amount of compound 1 and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant).13 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0044] Conjoint administration contemplates that the second therapeutic agent can be administered concomitantly, prior to, or after administration of compound 1.

[0045] In certain embodiments, compound 1 and the second therapeutic agent are administered concomitantly. In certain embodiments, compound 1 and the second therapeutic agent are administered concomitantly in two separate formulations. In certain embodiments, compound 1 and the second therapeutic agent are administered concomitantly in the same formulation.

[0046] In certain embodiments, compound 1 and the second therapeutic agent are administered sequentially. In certain embodiments, compound 1 is administered prior to administration of the second therapeutic agent. In certain embodiments, compound 1 is administered at least 1 hour before the second therapeutic agent, e.g., 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week or more before the second therapeutic agent.

[0047] In certain embodiments, compound 1 is administered after administration of the second therapeutic agent. In certain embodiments, compound 1 is administered at least 1 hour after the second therapeutic agent, e.g., 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week or more after the second therapeutic agent.

[0048] In certain embodiments, the second therapeutic agent is an antidepressant. In certain embodiments, the antidepressant is a selective serotonin reuptake inhibitor (SSRI). Exemplary SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, zimelidine, and salts of the foregoing.

[0049] In certain embodiments, the antidepressant is a serotonin modulator, such as vilazodone, trazodone, nefazodone, or vortioxetine.

[0050] In certain embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor (SNRI), e.g., venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, sibutramine, or tramadol.

[0051] In certain embodiments, the antidepressant is a selective serotonin-norepinephrine reuptake inhibitor (SNDRI), such as toludesvenlafaxine (ansofaxine), bicifadine, centanafadine, amitifadine, tesofensine, nefazodone, mazindol, sibutramine, nefopam, venlafaxine, ketamine, and esketamine.14 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0052] In certain embodiments, the antidepressant is a norepinephrine dopamine reuptake inhibitor (NDRI), such as amineptine, bupropion, desoxypipradrol, dexmethylphenidate, difemetorex, fencamfamine, fencamine, lefetamine, methylphenidate, nomifensine, pipradrol, prolintane, and solriamfetol.

[0053] In certain embodiments, the antidepressant is a tricyclic, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, loxapine, nortriptyline, olanzapine, protriptyline, quetiapine, and trimipramine.

[0054] In certain embodiments, the antidepressant is selected from aptazapine, esmirtazapine, benzoctamine, maprotiline, mianserin, mirtazapine, oxaprotiline, and setiptiline.

[0055] In certain embodiments, the antidepressant is a neurosteroid, such as allopregnanolone, brexanolone, ganaxolone, or zuranolone.

[0056] In certain embodiments, the antidepressant is an MAO inhibitor, such as phenelzine, isocarboxazid, selegiline, or tranylcypromine.

[0057] In another aspect, the present disclosure provides a method of treating a psychological disease or disorder (e.g., postpartum depression) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of compound 1, wherein the subject (a) has been on a stable regimen of at least one SSRI for at least 30 days prior to administration of compound 1 or (b) has been on established psychotherapy for at least 30 days prior to administration of compound 1.

[0058] In certain embodiments, the psychological disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

[0059] In certain embodiments, the psychological disease or disorder is selected from depression, MDD, PPD, and drug-resistant depression. In certain embodiments, the psychological disease or disorder is PPD.15 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0060] In certain embodiments, the subject is female. In certain embodiments, the subject is a human female. In certain embodiments, the subject is a female that is at least 18 years old.

[0061] In certain embodiments, the subject is no more than 15 months postpartum, e.g., no more than 14 months postpartum, no more than 13 months postpartum, no more than 12 months postpartum, no more than 11 months postpartum, no more than 10 months postpartum, no more than 9 months postpartum, no more than 6 months postpartum, or no more than 3 months postpartum. In certain embodiments, the subject is from 1 to 15 months postpartum, e.g., from 1 to 12 months, from 1 to 9 months, from 1 to 6 months, from 1 to 3 months, from 3 to 15 months, from 3 to 12 months, from 3 to 9 months, from 3 to 6 months, from 6 to 15 moths, from 6 to 12 months, from 6 to 9 months, from 9 to 15 months, from 9 to 12 months, or from 12 to 15 months postpartum.

[0062] In certain embodiments, the subject is not breastfeeding.

[0063] In certain embodiments, the subject has been diagnosed with PPD, i.e., the subject experienced a major depressive episode that began at any time during the period starting at the beginning of the second trimester (>14 weeks) of pregnancy through 4 weeks following delivery, confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders Clinical Trial Version (SCID-5-CT).

[0064] In certain embodiments, the subject is diagnosed with PPD prior to administration of compound 1 (administration of compound 1 = Day 0). In certain embodiments, the subject is diagnosed with PPD in the 21 days prior to administration of compound 1 (Day -1 to Day -21). In certain embodiments, the subject is diagnosed with PPD according to the SCID-5-CT prior to administration of compound 1. In certain embodiments, the subject is diagnosed with PPD according to SCID-5-CT in the 21 days prior to administration of compound 1.

[0065] In certain embodiments, the subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20 when evaluated on Day 0 prior to administration of compound 1. In certain embodiments, the subject has a MADRS score of 20 or higher, 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, or 32 or higher when evaluated on Day 0 prior to administration of compound 1. In certain embodiments, the subject has a MADRS score from 20 to 34 when evaluated on Day 0 prior to administration of compound 1. In certain embodiments, the subject has a MADRS score of less than or equal to 30 when evaluated on Day 0 prior to 16 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)administration of compound 1. In certain embodiments, the subject has a MADRS score of greater than or equal to 30 when evaluated on Day 0 prior to administration of compound 1.

[0066] In certain embodiments, the subject has experienced symptoms of depression prior to administration of compound 1. In certain embodiments, the subject has experienced symptoms of depression in the 21 days prior to administration of compound 1 (Day -1 to Day -21).

[0067] In certain embodiments, the subject has experienced symptoms of depression according to the Hamilton Rating Scale for Depression (HAMD-17), when the subject’s HAMD-17 score is evaluated in the 21 days prior to administration of compound 1. In certain embodiments, the subject has a HAMD-17 score of 24 or higher when the subject is evaluated in the 21 days prior to administration of compound 1. In certain embodiments, the subject has a HAMD-17 score of 20 or higher, 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, or 32 or higher when the subject is evaluated in the 21 days prior to administration of compound 1. In certain embodiments, the subject has a HAMD-17 score from 20 to 34 when the subject is evaluated in the 21 days prior to administration of compound 1.

[0068] In certain embodiments, the subject has a Clinical Global Impression-Severity (CGI-S) score (which grades severity of symptoms) of at least 3 (mildly ill) when the subject is evaluated in the 21 days prior to administration of compound 1 (Day -1 to Day -21), e.g., a CGI-S score of at least 4 (moderately ill), at least 5 (markedly ill), at least 6 (severely ill), or 7 (most extremely ill).

[0069] In certain embodiments, the subject is diagnosed with PPD and experiences symptoms of depression prior to administration of compound 1. In certain embodiments, the subject experiences symptoms of PPD for at least 1 month prior to administration of compound 1, at least 2 months prior to administration of compound 1, at least 3 months prior to administration of compound 1, at least 4 months prior to administration of compound 1, at least 5 months prior to administration of compound 1, at least 6 months prior to administration of compound 1, at least 7 months prior to administration of compound 1, at least 8 months prior to administration of compound 1, at least 9 months prior to administration of compound 1, at least 10 months prior to administration of compound 1, at least 11 months prior to administration of compound 1, at least 12 months prior to administration of compound 1, at least 13 months prior to administration of compound 1, at least 14 months prior to administration of compound 1, at least 15 months prior 17 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)to administration of compound 1, at least 16 months prior to administration of compound 1, at least 17 months prior to administration of compound 1, at least 18 months prior to administration of compound 1, at least 19 months prior to administration of compound 1, at least 20 months prior to administration of compound 1, at least 21 months prior to administration of compound 1, at least 22 months prior to administration of compound 1, at least 23 months prior to administration of compound 1, or at least 24 months prior to administration of compound 1.

[0070] In certain embodiments, the subject is diagnosed with PPD according to SCID-5-CT and experiences symptoms of depression as determined by the subject’s HAMD- 17 score and / or CGI-S prior to administration of compound 1. In certain embodiments, the subject is diagnosed with PPD according to SCID-5-CT, has a HAMD- 17 score of 24 or higher, and / or has a CGT-S score of at least 3 prior to administration of compound 1. In certain embodiments, when the subject is evaluated in the 21 days prior to administration of compound 1 (Day -1 to Day -21), the subject is diagnosed with PPD according to SCID-5-CT, has a HAMD-17 score of 24 or higher, and / or has a CGI-S score of at least 3.

[0071] In certain embodiments, the subject does not have a history of treatment-resistant depression within the current PPD episode as defined by having previously failed to respond to adequate courses (e.g., doses for >4 weeks) of pharmacotherapy from >2 different classes of antidepressants.

[0072] In certain embodiments, the subject has not received a serotonin-norepinephrine reuptake inhibitor (SNRI) to prior to administration of compound 1, e g., in the 14 days prior to administration of compound 1. In certain embodiments, the subject has not received a SNRI for at least 30 days prior to administration of compound 1.

[0073] In certain embodiments, the subject has not used a psychedelic prior to administration of compound 1. Psychedelics include, but are not limited to, psilocybin, ayahuasca, mescaline, kambo, yopo, ibogaine, 5-MeO-DMT, lysergic acid diethylamide, N, N-dimethyltryptamine, MDMA, Syrian Rue or other psychedelic agents or mixtures in their synthetic or naturally occurring. In certain embodiments, the subject has not used a psychedelic in the month prior to administration of compound 1. In certain embodiments, the subject has not used a psychedelic in the six months prior to administration of compound 1. In certain embodiments, the subject has not used a psychedelic in the year prior to administration of compound 1.18 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0074] In certain embodiments, the subject has not used psychoactive medication or a medication with monoamine oxidase activity (such as isocarboxazid, phenelzine, selegiline or tranylcypromine, linezolid, and methylene blue); antipsychotics, including haloperidol, or lithium; amphetamines; opioids; or other drugs with potential to precipitate serotonin-relate adverse reactions (see Table 3) prior to administration of compound 1, e.g., in the 28 days prior to administration of compound 1.

[0075] In certain embodiments, the subject has not used synthetic or naturally occurring cannabinoids prior to administration of compound 1.

[0076] In certain embodiments, the subject has not used ketamine or esketamine prior to administration of compound 1, e.g., in the 90 days prior to administration of compound 1.

[0077] In certain embodiments, the subject has been on a stable regimen of a SSRI for at least 30 days prior to administration of compound 1, e.g., at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 or more months prior to administration of compound 1. Exemplary SSRIs include citalopram, escital opram, fluoxetine, fluv oxamine, paroxetine, sertraline, indalpine, and zimelidine.

[0078] In certain embodiments, the subject has been on established psychotherapy for at least 30 days prior to administration of compound 1, e.g., at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 or more months prior to administration of compound 1.Exemplary psychotherapies include cognitive behavioral therapy (CBT) (e.g., dialectical behavior therapy (DBT), rational emotive behavior therapy (REBT), acceptance and commitment therapy (ACT)), behavioral therapy (e.g., systematic desensitization, aversion therapy, flooding), psychodynamic therapy, humanistic therapy (e.g., gestalt therapy, personcentered therapy, existential therapy), interpersonal therapy, and supporting therapy.

[0079] In certain embodiments, compound 1 is administered in a medical facility (e.g., hospital, out-patient care, doctor’s office, or clinic). In certain embodiments, the subject remains in the medical facility for at least 8 hours following administration of compound 1, e.g., for observation to ensure that the subject is ready to discharge. In certain embodiments, the subject remains in the medical facility for a least 12 hours, at least 16 hours, at least 20 hours, or at least 24 hours following administration of compound 1.19 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0080] Tn certain embodiments, compound 1 is administered to the subject by a medically trained professional, e.g., a pharmacist, nurse, or doctor.

[0081] In certain embodiments, compound 1 is administered to the subject via injection, e.g., subcutaneous injection. In certain embodiments, compound 1 is administered to the subject as a zwitterion.

[0082] In certain embodiments, compound 1 is administered in the form of a solution suitable for injection, e g., intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous injections. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle free injectors and infusion techniques.

[0083] In certain embodiments, compound 1 is administered to the subject as a zwitterion by subcutaneous injection. In certain embodiments, compound 1 is administered to the subject by subcutaneous injection as a zwitterion in the form of a solution.

[0084] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and pH adjusting or buffering agents (preferably to a pH of from 3.0 and 7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.5), but, for some applications, they may be more suitably formulated as a sterile non aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen free water or pre-fabricated, ready-to-mix aqueous buffer. Osmotic agents may be included to control tonicity.

[0085] The preparation of parenteral kits for reconstitution at point-of-care under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0086] A typical injectable solution is produced by aseptically placing at least one of the compounds of the present invention (e g., 33 mg of the HC1 salt of compound 1) into a vial as a sterile filtered solution, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with, for example, 2 mL of physiological saline for injection, optionally with an appropriate amount of osmotic complements and pH adjusters to achieve a slightly acidic to neutral pH (e.g. pH 4-7), to produce an injectable preparation with low irritation but retain solubility and / or stability of the prodrug.20 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0087] In certain embodiments, from 1 mg to 60 mg of compound 1 (calculated as the free base or HCl salt) is administered to the subject in a single dose, e.g., from 1 mg to 50 mg, from 1 mg to 40 mg, from 1 mg to 30 mg, from 1 mg to 20 mg, from 10 mg to 50 mg, from 10 mg to 40 mg, from 10 mg to 30 mg, from 20 mg to 50 mg, from 20 mg to 40 mg, from 20 mg to 30 mg, from 30 mg to 60 mg, from 30 mg to 50 mg, from 30 mg to 40 mg, from 40 mg to 60 mg, from 40 mg to 50 mg, or from 50 mg to 60 mg. In certain embodiments, 30 mg compound 1 (calculated as the free base) or 33 mg compound 1 (calculated as the HCl salt) is administered to the subject in a single dose. In certain embodiments, 1.5 mg of compound 1 (calculated as the free base) is administered to the subject in a single dose.

[0088] In certain embodiments, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of compound 1 (calculated as the free base) is administered to the subject in a single dose.

[0089] In certain embodiments, from 1 mg / mL to 60 mg / mL of compound 1 (calculated as the free base or HCl salt) is administered to the subject in a single dose in the form of a solution, e.g., from 1 mg / mL to 50 mg / mL, from 1 mg / mL to 40 mg / mL, from 1 mg / mL to 30 mg / mL, from 1 mg / mL to 20 mg / mL, from 10 mg / mL to 50 mg / mL, from 10 mg / mL to 40 mg / mL, from 10 mg / mL to 30 mg / mL, from 20 mg / mL to 50 mg / mL, from 20 mg / mL to 40 mg / mL, from 20 mg / mL to 30 mg / mL, from 30 mg / mL to 60 mg / mL, from 30 mg / mL to 50 mg / mL, from 30 mg / mL to 40 mg / mL, from 40 mg / mL to 60 mg / mL, from 40 mg / mL to 50 mg / mL, or from 50 mg / mL to 60 mg / mL. In certain embodiments, 30 mg / mL compound 1 (calculated as the free base) or 33 mg / mL compound 1 (calculated as the HCl salt) is administered to the subject in a single dose in the form of a solution. In certain embodiments, 1.5 mg / mL compound 1 (calculated as the free base) or 1.65 mg / mL compound 1 (calculated as the HCl salt) is administered to the subject in a single dose in the form of a solution.

[0090] In certain embodiments, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, or 60 mg / mL of compound 1 (calculated as the free base) is administered to the subject in a single dose in the form of a solution.21 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0091] In certain embodiments, the dose can be divided into two or more parts, e.g., to alleviate any anxiety relative to therapy. For example, the medical profession may choose to divide the therapeutic dose and thereby reduce the initial onset of psychoactivity before applying the full complement of the dosage to achieve the full effect.

[0092] In certain embodiments, the subject exhibits reduced depressive symptoms following administration of compound 1 compared to the subject’s depressive symptoms prior to treatment. In certain embodiments, the subject has a lower MADRS score following administration of compound 1 compared to the subject’s MADRS score on Day 0 prior to administration of compound 1. In certain embodiments, the subject’s MADRS score 7 days after administration of compound 1 is reduced by at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, at least 24 points, at least 25 points, at least 26 points, at least 27 points, at least 28 points, at least 29 points, at least 30 points, at least 31 points, at least 32 points, at least 33 points, at least 34 points, at least 35 points, at least 36 points, at least 37 points, at least 38 points, at least 39 points, at least 40 points, at least 41 points, at least 42 points, at least 43 points, at least 44 points, at least 45 points, at least 46 points, at least 47 points, at least 48 points, at least 49 points, or at least 50 points compared to the subject’s MADRS score on Day 0 prior to administration of compound 1.

[0093] In certain embodiments, the subject’s MADRS score following administration of compound 1 is reduced by at least 50% compared to the subject’s MADRS score prior to administration of compound 1 (baseline), e.g., at least 60%, at least 70%, at least 80%, or at least 90% reduced. In certain embodiments, the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s MADRS score following administration of compound 1 is evaluated 1 day after administration of compound 1 (Day 1). In certain embodiments, the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s MADRS score following administration of compound 1 is evaluated 7 days after administration of compound 1 (Day 7). In certain embodiments, the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s MADRS score following administration of compound 1 is evaluated 14 days after administration of compound 122 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)(Day 14). Tn certain embodiments, the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s MADRS score following administration of compound 1 is evaluated 28 days after administration of compound 1 (Day 28). In certain embodiments, the subj ect’ s MADRS score on one or more of Day 1, Day 7, Day 14 or Day 28 is reduced by at least 50% compared to the subject’s baseline MADRS score (Day 0). In certain embodiments, the subject’s MADRS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.

[0094] In certain embodiments, the subject’s MADRS score is 10 or less (i.e., consistent with remission) following administration of compound 1, e.g., a MADRS score of 10 or less, 8 or less, 6 or less, 4 or less, 2 or less, or 0. Tn certain embodiments, the subject’s MADRS score is 10 or less 7 days after administration of compound 1 (Day 7).

[0095] In certain embodiments, the subject’s Clinical Global Impression-Improvement (CGI-I) score demonstrates improvement in depressive symptoms following administration of compound 1, e.g., 1, 7, or 28 days following administration of compound 1 (Day 1, Day 7 or Day 28). In certain embodiments, the subject’s CGI-I score is 3 (minimally improved) or less following administration of compound 1, e.g., 1, 7, or 28 days following administration of compound 1 (Day 1, Day 7 or Day 28). In certain embodiments, the subject’s CGI-I score is at least 2 (much improved) or less following administration of compound 1, e.g., 1, 7, or 28 days following administration of compound 1 (Day 1, Day 7 or Day 28). In certain embodiments, the subject’s CGI-I score is 1 (very much improved) following administration of compound 1, e.g., 1, 7, or 28 days following administration of compound 1 (Day 1, Day 7 or Day 28).

[0096] In certain embodiments, the subject’s Clinical Global Impression-Severity (CGI-S) score following administration of compound 1 is improved compared to the subject’s CGI-S score prior to administration of compound 1 (baseline). Improvement with respect to CGI-S score refers to a later timepoint score that is lower than the baseline score. In certain embodiments, the subject’s CGI-S score improves from a baseline score of 4 (moderately ill), 5 (markedly ill), 6 (severely ill), or 7 (extremely ill) to a CGI-S score of 1 (normal), 2 (borderline ill), or 3 (mildly ill) following administration of compound 1. In certain embodiments, the subject’s CGI-S score following administration of compound 1 is reduced by at least 1 compared to the subject’s baseline CGI-S score, e.g., decreases by 1, 2, 3, 4, or 5 or more.23 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0097] In certain embodiments, the subject’s CGI-S baseline score is evaluated one day prior to administration of compound 1 (Day -1); and the subject’s CGI-S score following administration of compound 1 is evaluated 1 day after administration of compound 1 (Day 1). In certain embodiments, the subject’s CGI-S baseline score is evaluated one day prior to administration of compound 1 (Day -1); and the subject’s CGI-S score following administration of compound 1 is evaluated 7 days after administration of compound 1 (Day 7). In certain embodiments, the subject’s CGI-S baseline score is evaluated one day prior to administration of compound 1 (Day -1); and the subject’s CGI-S score following administration of compound 1 is evaluated 28 days after administration of compound 1 (Day 28).

[0098] In certain embodiments, the subject’s Edinburgh Postnatal Depression Scale (EPDS) score following administration of compound 1 is improved compared to the subject’s EPDS score prior to administration of compound 1 (baseline). Improvement with respect to EPDS score refers to a later timepoint score that is lower than the baseline score. In certain embodiments, the subject’s EPDS score improves from a baseline score of 12 or greater (indicative of a mother suffering from depression) to an EDPS score of less than 12 following administration of compound 1. In certain embodiments, the subject’s EPDS baseline score is evaluated from 2 to 21 days prior to administration of compound 1 (Days -2 to -21); and the subject’s EPDS score following administration of compound 1 is evaluated 7 days after administration of compound 1 (Day 7).

[0099] In certain embodiments, the subject’s Patient Health Questionnaire (PHQ-9) score following administration of compound 1 is improved compared to the subject’s PHQ-9 score prior to administration of compound 1 (baseline). Improvement with respect to PHQ-9 score refers to a later timepoint score that is lower than the baseline score (5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe, and 20 or higher = severe depression).

[0100] In certain embodiments, the subject’s PHQ-9 score following administration of compound 1 is consistent with mild or moderate depression. In certain embodiments, the subject’s PHQ-9 score is reduced from a baseline score consistent with moderately severe depression to a PHQ-9 score consistent with mild or moderate depression following administration of compound 1. In certain embodiments, the subject’s PHQ-9 score improves from a baseline score consistent with severe depression to a PHQ-9 score consistent with mild or24 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)moderate depression following administration of compound 1. Tn certain embodiments, the subject’s PHQ-9 baseline score is evaluated from 2 to 21 days prior to administration of compound 1 (Days -2 to -21); and the subject’s PHQ-9 score following administration of compound 1 is evaluated 14 days after administration of compound 1 (Day 14). In certain embodiments, the subject’s PHQ-9 baseline score is evaluated from 2 to 21 days prior to administration of compound 1 (Days -2 to -21); and the subject’s PHQ-9 score following administration of compound 1 is evaluated 28 days after administration of compound 1 (Day 28).

[0101] In certain embodiments, the subject exhibits reduced anxiety symptoms following administration of compound 1 compared to the subject’s anxiety symptoms prior to administration of compound 1 (baseline).

[0102] In certain embodiments, the subject’s Hamilton Rating Scale for Anxiety (HAM-A) score following administration of compound 1 is improved compared to the subject’s HAM-A score prior to administration of compound 1 (baseline). Improvement with respect to HAM-A score refers to a later timepoint score that is lower than the baseline score. In certain embodiments, the subject’s HAM-A score is reduced from a score of 25 or higher (moderate to severe anxiety) to less than 25 following administration of compound 1, e.g., a HAM-A of 18 to 24 (mild to moderate anxiety) or less than 17 (anxiety). In certain embodiments, the subject’s HAM-A score is reduced from a score of 30 or higher (moderate to severe anxiety) to less than 25 following administration of compound 1, e.g., a HAM-A of 18 to 24 (mild to moderate anxiety) or less than 17 (anxiety). In certain embodiments, the subject’s HAM-A score is 30 or less following administration of compound 1. In certain embodiments, the subject’s HAM-A score is 25 or less following administration of compound 1.

[0103] In certain embodiments, the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s HAM-A score following administration of compound 1 is evaluated 1 day after administration of compound 1 (Day 1). In certain embodiments, the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s HAM-A score following administration of compound 1 is evaluated 7 days after administration of compound 1 (Day 7). In certain embodiments, the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s HAM-A score25 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)following administration of compound 1 is evaluated 14 days after administration of compound 1 (Day 14). In certain embodiments, the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and the subject’s HAM-A score following administration of compound 1 is evaluated 14 days after administration of compound 1 (Day 14).

[0104] In certain embodiments, the subject has a complete mystical experience following administration of compound 1, i.e., has a Mystical Experience Questionnaire (MEQ) total score >60%. In certain embodiments, the subject’s MEQ score is evaluated from prior to discharge at 8 hours or later following administration of compound 1.

[0105] In certain embodiments, the subject exhibits improved maternal behaviors following administration of compound 1 compared to the subject’s maternal behaviors prior to administration of compound 1 (baseline).

[0106] In certain embodiments, the subject’s Barkin Index of Maternal Functioning (BIMF) score is improved following administration of compound 1 compared to the subject’s BIMF score prior to administration of compound 1 (baseline). Improvement with respect to BIMF refers to a later timepoint score that is higher than the baseline score. In certain embodiments, the subject’s BIMF baseline score is evaluated from 2 to 21 days prior to administration of compound 1 (Days -2 to -21); and the subject’s BIMF score following administration of compound 1 is evaluated 7 days after administration of compound 1 (Day 7). In certain embodiments, the subject’s BIMF baseline score is evaluated from 2 to 21 days prior to administration of compound 1 (Days -2 to -21); and the subject’s BIMF score following administration of compound 1 is evaluated 28 days after administration of compound 1 (Day 28).6. EXAMPLES6.1. EXAMPLE 1 - A Multicenter, Randomized, Double-Blind, Parallel-Group Dose-Controlled Study Evaluating the Safety and Efficacy of Compound 1 for Injection in the Treatment of Patients with Postpartum Depression (PPD)6.1.1. Summary

[0107] This was a Phase 2, multicenter, randomized, double-blind, parallel-group,dose-controlled study evaluating the safety and efficacy of compound 1 (30 mg and 1.5 mg), the26 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)study drug, in the treatment of adult female patients with PPD. This study was conducted at approximately 35 study centers in the United States.

[0108] A schema of the trial is provided in FIG. 1. A schedule of Activities (SoA) for the trial is provided in FIG. 2.

[0109] Approximately 72 patients (36 per dose group) were randomized to receive 30 mg compound 1 or 1.5 mg compound 1 in a 1:1 manner, administered as a single-dose subcutaneous (SC) injection in a clinic setting. This study had four periods: a Screening Period of up to 21 days; a 2-day Baseline Period consisting of baseline assessments on Day -1 and up through pre-dosing on Day 0, during which eligibility was confirmed; immediately followed by the Treatment Period, which began with study drug administration and during which patients were monitored in-clinic for a minimum of 8 hours before being discharged on Day 0; and, after the Treatment Period was completed and the patient was discharged from the clinic, a 28-day Follow-Up Period was carried out, where efficacy and safety assessments were performed periodically.Objectives and Endpoints:

[0110] The objectives and endpoints of the study are provided in Table 1.Table 1. Endpoints and ObjectivesObjectives Endpoints PrimaryTo evaluate if 30 mg compound 1 reduced • Change from baseline at Day 7 in depressive symptoms compared to 1.5 mg Montgomery-Asberg Depression Rating Scale compound 1 in patients with PPD. (MADRS) total scoreSecondaryTo evaluate the time-course and overall response • Change from baseline at Day 1, Day 14, and of 30 mg compound 1 compared to 1.5 mg Day 28 in MADRS total score compound 1 in patients with PPD. • Percentage of patients with MADRS response (>50% reduction in score from baseline) at Day 7• Percentage of patients with MADRS remission (score <10) at Day 7• Clinical Global Impression-Improvement (CGI-I) at Day 1, Day 7, and Day 2827 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Objectives Endpoints• Change from baseline in CGI-Severity (CGI- S) Day 1, Day 7, and Day 28To evaluate if 30 mg compound 1 reduced anxiety • Changes in total score from baseline in symptoms compared to 1.5 mg compound 1 in Hamilton Anxiety Rating Scale (HAM-A) patients with PPD. total score at Day 7To evaluate the safety of 30 mg compound 1 Incidence of Treatment-emergent Adverse compared to 1.5 mg compound 1 in patients with Events (TEAEs) by frequency, severity, and PPD. seriousnessOtherTo further evaluate the safety of 30 mg compound • Clinical laboratory measures1 compared to 1.5 mg compound 1 in patients • Vital signswith PPD.• Electrocardiogram (ECG) parameters• Concomitant medication usage• Incidence of suicidal ideation or behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)• Change from baseline in psychosis as assessed by the Brief Psychiatric Rating Scale - positive symptoms subscale (BPRS+) To evaluate the quantitative and qualitative • Mystical Experience Questionnaire (MEQ-4) psychoactive experience / response to compound 1. • Challenging Experience Questionnaire (CEQ- 7)To further evaluate if 30 mg compound 1 reduced • Change from baseline at Day 7 in Edinburgh depressive symptoms compared to 1.5 mg Postnatal Depression Scale (EPDS) total score compound 1 in patients with PPD. • Change from baseline at Day 14 in Patient Health Questionnaire (PHQ-9) total score To evaluate if 30 mg compound 1 improved • Change from baseline at Day 7 in Barkin maternal behaviors compared to 1.5 mg Index of Maternal Functioning (BIMF) total compound 1 in patients with PPD. scoreTo evaluate if 30 mg compound 1 improved • Change from baseline in Short Form 36 general health status compared to 1.5 mg Health Survey (SF-36) acute version total compound 1 in patients with PPD. scoreTo evaluate adequacy of the blind to randomized • Assessment of treatment assignment by treatment. patients and efficacy ratersScreening Period:

[0111] The Screening Period began when a patient provided written informed consent prior to any study-related assessments. Patients were required to identify a designated caregiver to assist with infant care on the day of study treatment and for up to 24 hours post-dose.28 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0112] During the Screening Period, patients were assessed for study eligibility, including confirmation of diagnosis of PPD via administration of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders Clinical Trial Version (SCID-5-CT). Symptom severity was assessed using the Hamilton Depression Rating Scale (HAMD-17) with the Structured Interview Guide for the Hamilton Depression Rating Scale-17-Item Version (SIGH-D-17), as well as the Clinical Global Impression-Severity (CGI-S) score.Baseline Period:

[0113] Pre-dose assessments were completed as part of the Baseline Visits (Day -1 and Day 0) to ensure continued eligibility and suitability of patients for dosing. Eligible and suitable patients were randomized on the day of dosing (Day 0) to one of two dose levels of compound 1 (30 mg or 1.5 mg), stratified by MADRS baseline total score into two groups (total score < 30 and > 30).Treatment Period:

[0114] The study drug was prepared and administered as a SC injection.

[0115] The dosing session was supported by two qualified Session Monitors and was video-recorded for training and adherence monitoring.

[0116] Patients remained in the clinic under general observation for post-dose routine safety monitoring and discharge readiness per the Schedule of Activities (SoA) for 8 hours.

[0117] Once deemed ready for discharge, patients were allowed to return home and were escorted by a trusted friend, family member, or caregiver.

[0118] The 8-hour post-dose discharge-readiness evaluation was a clinical examination and included assessment of the patient’s psychiatric and physical status and associated health parameters, including vital signs and the status of any treatment-emergent adverse events (AEs).Follow-Up Period:

[0119] Efficacy and safety assessments were performed periodically during the study (FIGs.2A-2B)29 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0120] The primary efficacy measure, the MADRS, was completed using the Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA) throughout the study. The Hamilton Anxiety Rating Scale (HAM-A) (using the Structured Interview Guide for the Hamilton Anxiety Scale [SIGH-A]), Brief Psychiatric Rating Scale—positive symptoms subscale (BPRS+), Columbia-Suicide Severity Rating Scale (C-SSRS), and Clinical Global Impression–Severity / Clinical Global Impression–Improvement (CGI-S / CGI-I) were also completed.

[0121] Two integration sessions were conducted, one as part of the follow-up procedures on Day 1 and the other on Day 7. Efficacy ratings were completed prior to each integration session.Study Arms and Duration:

[0122] Arm 1: Compound 1 administered by SC injection in the upper arm at a single dose of 30 mg (1.0 mL).

[0123] Arm 2: Compound 1 administered by SC injection in the upper arm at a single dose of 1.5 mg (0.05 mL).

[0124] Consistent with psychedelic clinical trials, the low compound 1 dose arm (Arm 2) was used as a control rather than placebo to minimize the likelihood of functional unblinding of site staff and patients. The active-dose control of compound 1 (1.5 mg) was selected to address concerns over the use of a traditional placebo control and was anticipated to be a subperceptual dose of compound 1.

[0125] The study duration for each patient was up to 53 days including an up to 21 -day screening window.6.1.2. Patient PopulationInclusion Criteria

[0126] Patients were eligible to be included in the study only if all of the following criteria applied:30 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)1. Was female aged 18 to 45 years, inclusive, at the time of signing the Informed Consent Form (ICF).2. Was <15 months postpartum at Screening and met DSM-5 criteria for PPD: experiencing a major depressive episode that began at any time during the period starting at the beginning of the second trimester (>14 weeks) of pregnancy through 4 weeks following delivery, confirmed by the SCID-5-CT.3. Had a HAMD-17 total score of >24 at Screening and Baseline (Day -1 prior to dosing). 4. Was not receiving and was willing to delay the use of any psychotropic pharmacotherapy regimens (including antidepressant or antianxiety medication) and / or psychotherapy (unless already on a stable, established regimen of SSRIs and / or psychotherapy for at least 30 days prior to Screening) until Day 7 study assessments had been completed. Patients were not required to discontinue current, adequate psychotropic treatment(s) for the sole purpose of enrollment into the study.5. Had ceased breastfeeding at Screening (i.e., had already fully and permanently weaned their infantfs] from breastfeeding).6. Was using an effective and appropriate method of contraception at Screening and agreed to continue using such a method throughout the duration of the study. The method of contraception was documented for each patient.7. Had a negative pregnancy test at Screening and Day 0 prior to study drug administration.8. Was capable of giving signed informed consent which included compliance with the requirements and restrictions listed in the ICF and in this protocol.9. Was willing and able to nominate a trusted caregiver who:a. Could assist in providing support, care, and attention to the patient’s infant(s) for the entirety of the dosing day (Day 0) through a 24-hour post-dose (Day 1) visit.10. Agreed to adhere to the study requirements.Exclusion Criteria

[0127] Patients were excluded from the study only if any of the following criteria applied:31 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)1. Had a history or had active postpartum psychosis per Investigator assessment.2. Had a history of treatment-resistant depression within the current postpartum depressive episode as defined by having previously failed to respond to adequate courses (e.g., doses for >4 weeks) of pharmacotherapy from >2 different classes of antidepressants.3. Had a significant risk of suicide according to the C-SSRS at Screening or Baseline (Day -1) or had attempted suicide within 12 months prior to the Screening Visit.a. Had acute suicidality as evidenced by a response of “yes” for Question 4 (“In the Past Year”) or Question 5 (“In the Past Year”) on the C-SSRS, indicating active suicidal ideation with any intent to act at Screening or Baseline (Day 0).b. Had a history of suicidal behavior such that a determination of “yes” was made on the Suicidal Behavior section of the C-SSRS (“In the Past Year”) for “Actual Attempt,” “Interrupted Attempt,” “Aborted Attempt,” or “Preparatory Acts or Behavior.”4. Had active or medical history of bipolar disorder, schizophrenia, schizoaffective disorder, psychotic disorder and / or borderline personality disorder, as assessed by the SCID-5-CT and per Investigator’s judgment), or first-degree family history of psychosis or bipolar disorder.5. Had a medically significant condition rendering unsuitability for the study (e g., neurologic disorders, diabetes, epilepsy, severe cardiovascular disease including patients with preexisting valvulopathy or pulmonary hypertension, uncontrolled thyroid dysfunction, hepatic or renal failure [e.g., creatinine clearance <30 mL / min], or uncontrolled hypertension) in the opinion of the Investigator.6. Had active or medical history of seizures other than childhood febrile seizures.7. Had a positive COVID-19 antigen test within 14 days of Treatment Day 0.8. Had a QTc interval prolongation at Screening of >450 msec 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).32 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)9. Had exposure to another clinical study involving study treatment within 30 days prior to Screening.10. Was administered electroconvulsive therapy (ECT) or transcranial magnetic stimulation within 90 days prior to Screening and / or planned to be administered ECT before the Study Day 28 Visit.11. Had previous use of psychedelics such as psilocybin, ayahuasca, mescaline, or LSD (with the exception of cannabis) within 12 months prior to Screening.12. Initiated new psychotherapy (cognitive behavioral therapy) within 30 days prior to Screening. Had no changes to stable psychotherapy, within 30 days prior to Screening. 13. Had a previous use of prohibited medications / agents as listed in Table 3.14. Had known sensitivity or intolerance to hallucinogenic or psychedelic substances, or potential rescue medications (e.g., short-acting benzodiazepines or standard of care for nausea or vomiting) as reported by the patient and / or determined by the Investigator.15. Had current (within the last 12 months) alcohol or substance use disorder or positive urine drug screen for illicit drugs (including cannabis) or drugs of abuse at Screening or Day 0. A positive test for cannabinoids (e.g., marijuana) at Screening did not exclude a patient if, after discussion with and evaluation by the Investigator, the patient agreed not to use any marijuana or other cannabinoid products during the study, and if allowed to participate, the patient tested negative for cannabinoids on Day 0. Any positive urine drug test was reviewed with patients to determine the pattern of use and eligibility was determined at the Investigator’s discretion in conjunction with the Medical Monitor.16. Patient who, as determined by the Investigator, was not otherwise considered a suitable study patient (i.e., extreme or significant complicating co-morbidities, past or current trauma, social stressors / instability and / or personal circumstances and behavior that might be incompatible with the establishment of rapport or safe exposure to compound 1).17. Was an immediate family member, study site employee, or was in a dependent relationship with a study site employee who was involved in the conduct of this study (e.g., spouse, parent, child, sibling) or who may have consented under duress.33 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Lifestyle Considerations

[0128] On the day of dosing, patients were instructed to have a light snack no later than 2 hours prior to dosing. A light meal was made available to patients toward the end of the dosing session (approximately 4-5 hours after dosing).

[0129] Patients were instructed to limit ingestion of caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before administration of the study drug (e.g., limited to no more than one cup of coffee on the day of dosing).

[0130] Patients were instructed to abstain from alcohol for 24 hours before administration of the study drug and to limit alcohol use to no more than one unit per day during participation in the study.

[0131] Patients who used tobacco products were instructed that use of such products was not permitted throughout the dosing session and until clinic discharge.6.1.3. Study Interventions

[0132] The drug product was a sterile lyophilized solid supplied in a single use vial ready for reconstitution with an aqueous sterile diluent (Table 2).

[0133] For the 30 mg compound 1 dosage level: 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 that contained 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).

[0134] For the 1.5 mg compound 1 dosage level: 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 that contained solubilized compound 1. The dose taken up from the vial for administration to the subject contained 1.5 mg compound 1 (calculated as the free base).Table 2. Study Interventions AdministeredIntervention Compound 1 for Injection DiluentName / LabelIntervention Lyophilized powder for subcutaneous Solution, 60 mM sodium phosphate Description injection, 30 mg / mL, Single Dose dibasic and 40 mM sodium chloride34 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Type Drug DiluentDose Formulation Each vial contained 33 mg of sterile, Each vial contained 1.1 mL of lyophilized compound 1 (HC1 salt) aqueous solution for injection of powder for injection. sodium phosphate dibasic (60 mM) Each vial was reconstituted with and sodium chloride (40 mM).1.1 mL of compound 1 Diluent toprovide 30 mg / mL of compound 1.Unit Dose 30 mg / mL compound 1 when diluted N / AStrength(s)awith 1.1 mL of diluent.Dosage Level] s) Single fixed dose depending on N / Atreatment assignment of:• 1.5 mg compound 1 (0.05 mL), or• 30 mg compound 1 (1.0 mL)Route of Subcutaneous injection N / AAdministrationUse Active Other: Diluent for Active Packaging and Compound 1 was packaged in labeled Diluent was packaged in labeled 2mL Labeling 2mL vials; multiple vials were vials; multiple vials were packaged packaged into a labeled box for into a labeled box for shipping to the shipping to the investigational site. investigational site.Packaging and labeling were not Packaging and labeling were not blinded. blinded.Storage and Frozen at - 25° to - 15°C (-13° to Room Temperature at 15°C to 25°C Handling 5 °F) (59°F to 77°F)ConditionsAppearance Compound 1 was a white / off white to Diluent was a clear solution,yellow lyophilized cake which when essentially free of visible particles or reconstituted became a clear, foreign material.colorless to yellow-brown solution,essentially free of visible particles orforeign material.aDoses are expressed throughout this protocol in accordance with the USP salt policy where 30 mg / mL compound 1 (free base) is equivalent to 33 mg / mL compound 1 (HC1 salt) and 1.5 mg / mL compound 1 (free base) is equivalent to 1.65 mg / mL compound 1 (HC1 salt).

[0135] The diluent, which was composed of sodium phosphate dibasic and sodium chloride, was used to solubilize and neutralize the HC1 salt when 1.1 mL of the diluent was added to the content of the vial, thereby producing compound 1 (zwitterion). The resulting solution had a pH between 4.5 to 5.5 and was ready for injection as a 30 mg / mL free base (equivalent to 33 mg / mL HC1 salt).35 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.3.1 Prior and Concomitant Therapy

[0136] All medications (prescription and over-the-counter [OTC]) taken within 30 days of study Screening were recorded along with reason for use, dates of administration, and dosage information (including dose and frequency). In addition, all historic use of psychedelic drugs was recorded, and all psychiatric medications taken within the last 2 years prior to Screening were recorded.

[0137] All medications (prescription and OTC) taken starting from the study Screening Period through End of Study were recorded along with reason for use (e.g., worsening of PPD symptoms), dates of administration, and dosage information (including dose and frequency).

[0138] Patients with worsening of symptoms as defined below could start treatment with antidepressants if needed after Day 7:• Patient was at significant risk of suicide (either according to the study physician’s judgment or defined as answering “yes” to suicidal ideation questions number 4 or 5 or answering “yes” to suicidal behavior within the framework of a C-SSRS assessment or defined as a score >5 on item 10 [suicidal thoughts] of the MADRS).• Acutely suicidal patients: patients who reported suicidal ideation or behavior per the Investigator judgment were be referred for appropriate medical care— OR—• CGI-I scores at Day 7 of 6 (much worse) or 7 (very much worse)— OR—• Was warranted for patient safety, in the opinion of the Investigator.

[0139] The medications described in Table 3 were prohibited within the timeframes indicated. Note that a full listing of other drugs with the potential to precipitate serotonin-related adverse reactions (which were excluded within 28 days prior to Screening) are provided as in Table 4.36 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 3. Prohibited MedicationsMedication Timeframe for Medication being Prohibited • Use of selective serotonin reuptake inhibitors Within 30 days prior to Screening and during (unless already on a stable regimen for 30 days study.prior to Screening) with the exception of doses>40 mg / day of citalopram (per exclusion criteria)• Use of serotonin-norepinephrine reuptake Within 14 days prior to Screening and during inhibitors the study.• Use of psychedelics such as psilocybin, Within 12 months prior to Screening and ayahuasca, mescaline, kambo, yopo, ibogaine, 5- during the study.MeO-DMT, lysergic acid diethylamide, N, N- Dimethyltryptamine, MDMA, Syrian Rue orother psychedelic agents or mixtures in theirsynthetic or naturally occurring form• Other psychoactive medication, or a medication Within 28 days prior to Screening and during with monoamine oxidase activity (such as the study.isocarboxazid, phenelzine, selegiline ortranylcypromine, linezolid. and methylene blue)• Antipsychotics, including haloperidol, or lithium• Use of amphetamines, opioids• Other drugs with the potential to precipitateserotonin-related adverse reactions (refer toTable 4)• Use of synthetic or naturally occurring From time of consent and throughout the cannabinoids study.• Use of ketamine or esketamine Within 90 days prior to Screening and during the study.Note for items in italics’. Episodic, low dose use of these listed medications for conditions, that otherwise did not exclude patients from participating in the study, were allowed during the 28 days prior to Screening provided that:• The investigator obtained sufficient information from the patient to confirm the dosage, reason, frequency and pattern of use as infrequent / occasional• The patient agreed to not use the medication during the study• The investigator obtained Sponsor and / or Study Medical Monitor approval in support of eligibility (provided that no other eligibility issues are present)37 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 4. Agents that Alone or in Conjunction with Other Serotonergic Agents Can Precipitate Serotonin-related Adverse ReactionsDrug Class List of Agents• AlmotriptanTriptans• Eletriptan• Frovatriptan• Naratriptan• Rizatriptan• Sumatriptan• ZolmitriptanMiscellaneous • Amphetamines (including: dextroamphetamine, methamphetamine)• Amphetamine derivatives (including: fenfluramine, dexfenfluramine, phentermine)• Mirtazapine• Cocaine• Meperidine• Tramadol• Pentazocine• Dextromethorphan• Sibutramine• Bupropion• Serotonin modulators (nefazodone, trazodone, vilazodone, and vortioxetine) • Cyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine)• St. John's wort (Hypericum perforatum)• 5-HT3receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)• Cyclobenzaprine• Methylphenidate, dexmethylphenidate• Nonselective MAO inhibitors (isocarboxazid, linezolid, phenelzine, Syrian rue [Peganum harmala, harmine], and tranylcypromine)• MAO-A inhibitors (methylene blue, moclobemide)38 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Drug Class List of Agents• MAO-B inhibitors (rasagiline, safinamide, and selegiline)• Buspirone• Ergot derivatives (including dihydroergotamine, ergotamine, methylergonovine)• Fentanyl• Lasmiditan• Lorcaserin• Metaxalone6.1.4. Study Procedures

[0140] Study procedures and their timing are summarized in the SoA (FIGs.2A-B) and below.Screening Period (Visit 1)

[0141] An ICF was signed by patients before any study-related assessments were performed. Eligibility was determined during the Screening Period (up to 3 weeks [Days -21 to -2]) and was confirmed through a central Eligibility Review conducted by the Study Medical Monitor and the Study Clinical Assessment Technologies (CAT) Clinician prior to Day 0.

[0142] At the initial Screening Visit (VI), assessments were performed by the designated site staff as noted below. Diagnosis of PPD was determined by the SCID-5-CT, with severity of symptoms established by the HAMD-17 and CGI-S completed by an Investigator or qualified site rater who did not serve as the blinded independent rater for the study. The patient also completed the first of two preparatory sessions, lasting approximately 30-60 minutes in person with a qualified Session Monitor. The preparatory sessions were intended to prepare and educate patients about dosing and post-dosing experiences and their management, as applicable.Baseline Period (Visits 2 and 3)

[0143] The Baseline Period began within approximately 3 weeks of Screening and was split over two visits, with assessments occurring at Day -1 (Visit 2) and prior to dosing on Day 0. Patients were contacted remotely at Day -1 and then returned to the clinic for pre-dose assessments on the day of dosing. The second preparatory session was scheduled as part of Visit 2 procedures and could be completed remotely with the LSM. Assessments to be completed at Day -1 were completed within a 4-day window of dosing on Day 0 to allow adequate time for confirmation of 39 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)eligibility by the Investigator. Dosing did not proceed until eligibility was confirmed based on results obtained and assessments completed after Screening.

[0144] Baseline Day 0 (Visit 3, pre-dose in-clinic): Baseline MADRS ratings on Day 0 were completed prior to any other efficacy assessments by a blinded, independent rater who was able to consistently rate the patient throughout the study. Patients were reminded of the importance of reporting their symptoms accurately prior to completion of the MADRS through use of a standardized script. Patients were not randomized until availability of the assigned appropriate LSM and Assistant Session Monitor (ASM) had been confirmed on the day of dosing.Treatment Period (Visit 3; 0 to 8 hours)

[0145] Dosing with study medication occurred on Day 0 after all pre-dose assessments and procedures had been completed. The study drug was prepared and administered as a subcutaneous (SC) injection by an unblinded pharmacist, nurse, or other appropriately trained and qualified designee.

[0146] After dosing, patients remained in the clinic for 8 hours under general observation for completion of post-dose assessments including safety monitoring and discharge readiness assessments per the SoA.

[0147] To ensure that compound 1 effects had fully subsided, patients were assessed for safety and discharge readiness by a medically qualified Investigator or designee.

[0148] At the 8-hour post-dose timepoint and once deemed ready for discharge, patients were allowed to go home and were escorted by a trusted friend, family member, or caregiver. The session monitor and / or medically qualified Investigator or designee checked in with the patient (and / or family member, as applicable) later in the evening to confirm that the patient was comfortable and stable.

[0149] If the patient’s clinical condition did not warrant discharge at the 8-hour post-dose timepoint, the patient was managed under standard of care until ready for discharge and confirmed by a medically qualified Investigator.

[0150] Assessments were performed as per the SoA.40 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Follow-up Period (Visits 4 to 10)

[0151] The 28-day Follow-Up Period included in-clinic visits at Days 1, 7, 14, and at the end of study at Day 28 for completion of efficacy assessments by the blinded independent rater and two integration sessions. For efficacy assessments, the MADRS was completed first by the blinded independent rater, preceded by a reminder of the importance of reporting symptoms accurately through use of a standardized script. Remote safety check-ins also occurred at Days 4, 10, and 21 as specified in the SoA.6.1.5. Efficacy Assessments6.1.5.1 Montgomery-Åsberg Depression Rating Scale (MADRS)

[0152] 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 was administered using the Structured Interview Guide for the MADRS (SIGMA). 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 was preceded by a standardized Reminder Script reminding patients to report their symptoms accurately at each timepoint in order to reduce potential “placebo” response.

[0153] The past week version of MADRS was administered. For visits where the visit window required it, a modified ‘since last evaluation’ version of the assessment was used.6.1.5.2 Hamilton Rating Scale for Depression (HAMD-17)

[0154] The HAMD-17 is a validated 17-item questionnaire administered by the clinician used to assess severity of, and change in, depressive symptoms in the past week. The questionnaire assesses core symptoms of depression, anxiety, and side effects of drug treatment on a scale of 0 to 50 with higher scores indicating more severe depression. For this study, the SIGH-D-17 was used to confirm symptoms severity for study entry; it was not considered an efficacy measure.41 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.5.3 Clinical Global Impression-Improvement (CGI-I) and Clinical Global Impression-Severity (CGI-S)

[0155] The Clinical Global Impression Scale is a clinician-rated instrument comprised of 3 global measures: severity of illness, global improvement, and efficacy index.

[0156] The CGI-I weighs the clinical impact of the identified symptom(s) on behavior and function and measures changes in psychopathology since the treatment was administered on a seven-point scale: “Compared to the patient's condition at admission / prior to treatment, this patient's condition is: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment);5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment.”

[0157] The CGI-S grades severity of symptoms on a scale from 1 (normal, not ill at all) to 7 (among the most extremely ill patients).6.1.5.4 Hamilton Rating Scale for Anxiety (HAM-A)

[0158] 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 were scored from 0 (not present) to 4 (very severe), for a total score ranging from 0 to 56. Scores <17 indicated mild anxiety, scores of 18 to 24 indicated mild to moderate anxiety, and scores of 25 to 30 or higher indicated moderate to severe anxiety. The Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) was used for this study.6.1.5.5 Structured Clinical Interview for DSM-5 Axis I Disorders (Clinical Trial Version)

[0159] The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for making major DSM-5 diagnoses. The SCID-5 was administered by a clinician or trained mental health professional who was familiar with the DSM-5 classification and diagnostic criteria. 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.42 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.5.6 Edinburgh Postnatal Depression Scale

[0160] The Edinburgh Postnatal Depression Scale (EPDS) is a validated 10-item patient-reported questionnaire developed to identify women who may have PPD. Each answer is given a score of 0 to 3 with a maximum score of 30 with higher scores indicating a more severe condition. Items of the scale correspond to various clinical depression symptoms, such as guilt feeling, sleep disturbance, low energy, anhedonia, and suicidal ideation. Mothers scoring above 10 or 11 (e g., 12 or 13) were likely to be suffering from depression.6.1.5.7 Patient Health Questionnaire-9 (PHQ-9)

[0161] The Patient Health Questionnaire-9 (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 is similar to the EPDS, but where the EPDS is designed to screen pregnant and postpartum women for depression, the PHQ-9 can be utilized for anyone. 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.

[0162] Each “not at all” response was scored as 0; each “several days” response was 1; each “more than half the days” response was 2; and each “nearly every day” response was 3. The sum value of these responses provided the total score with a higher score indicating more severe depression.6.1.5.8 Barkin Index of Maternal Functioning

[0163] The Barkin Index of Maternal Functioning (BIMF) is a validated 20-item patient-reported questionnaire that was designed to assess overall functioning in the context of new motherhood. The functional domains of social support, management, mother-child interaction, infant care, self-care, adjustment, and psychological wellbeing (of the mother) are addressed by the BIMF. The total score ranges from 0 to 120, with a score of 120 representing perfect functioning.Reported scores for the general population of non-depressed postpartum women range from 97.4 to 104.6.1.5.9 36- Item Short Form Survey43 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0164] The 36-Item Short Form Survey (SF-36) is a 36-item measure of health status that has undergone validation in many different disease states. The SF-36 is a patient-reported measure that covers 8 health dimensions including 4 physical health status domains (physical functioning, role participation with physical health problems [role-physical], bodily pain, and general health) and 4 mental health status domains (vitality, social functioning, role participation with emotional health problems [role-emotional], and mental health). In addition, 2 summary scores, physical component summary and mental component summary, are produced by taking a weighted linear combination of the 8 individual domains. Higher SF-36 scores indicate a better state of health.6.1.5.10 Placebo-Control Reminder Script (PCRS)

[0165] The Placebo-Control Reminder Script (PCRS)(© Hassman and Cohen, 2019, Version 5.0) educated 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 related to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differed from their experience with previous providers. To do this, the PCRS informed subjects that they were to be honest about their symptoms, site staff had no expectations of symptom improvement or worsening and would not be disappointed if they feel better, worse or the same, and asked participants to explain in their own words its content to ensure comprehension. Per the instructions on the PCRS, the efficacy scale rater read the script verbatim immediately before administering efficacy scale. The PCRS was 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.

[0166] In this study, the active control arm (low dose, 1.5 mg compound 1) was considered similar to a placebo in that it was being used to minimize the likelihood of functional unblinding of site staff and study participants. The PCRS was modified as necessary to help reduce participant expectation bias in receiving the low dose (similar to a placebo).6.1.5.11 Safety Assessments6.1.5.11.1 Physical Examination and Height

[0167] Full and targeted physical examinations were performed as indicated in the SoA. A comprehensive physical examination was conducted at Screening and included, at a minimum,44 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Brief physical examinations were symptom directed.

[0168] Height was recorded in inches and converted to centimeters at Screening.6.1.5.11.2 Vital Signs and Body Weight

[0169] Vital signs and body weight were performed as indicated in the SoA. Vital signs included heart rate, temporal temperature (degrees Celsius [°C] or Fahrenheit [°F]), supine blood pressure (systolic and diastolic) and supine pulse measurements. Supine recordings were made after the participant had been supine for at least 5 minutes and prior to blood collection for laboratory tests.

[0170] The body weight was recorded in pounds and converted to kilograms.6.1.5.11.3 Electrocardiogram

[0171] Twelve-lead electrocardiograms (ECGs) were performed as indicated in the SoA.

[0172] ECGs were recorded in the supine position, allowing 5 minutes of rest and before performing any venipuncture. ECGs were reviewed for any clinically relevant abnormalities by a central reader, and categorized as normal, borderline (abnormal, not clinically significant), or abnormal (clinically significant).

[0173] The intervals or derivatives of heart rate (bpm), PR-interval (msec), QRS-interval (msec), QT-interval (msec) and QTc interval (using Fridericia’s formula) were measured and captured in the database.6.1.5.11.4 Laboratory Parameters

[0174] Clinical laboratory tests were performed as indicated in the SoA.

[0175] The following laboratory tests were performed:• Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, red blood cell indices (mean corpuscular volume, mean corpuscular hemoglobin and percentage of reticulocytes), and white blood cell count (with differential).45 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)• Chemistry: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood urea nitrogen, calcium, creatinine, glucose (fasting), potassium, protein-total, sodium, total and direct bilirubin.• Urinalysis: bilirubin, blood, glucose, ketones, leukocyte esterase by dipstick, microscopic examination (if blood or protein was abnormal), nitrite, pH, protein, specific gravity, and urobilinogen.• Other screening tests: breathalyzer (alcohol) or urine (drug) screen (to include at minimum: amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, and opiates), COVID-19 antigen test, and serology (human immunodeficiency virus antibody, hepatitis B surface antigen, and hepatitis C virus antibody).

[0176] Laboratory samples were analyzed by a central laboratory to ensure consistent interpretation of results. The exceptions (i.e., tests performed in clinic) were: urine pregnancy test, urine drug screen, COVID-19 antigen test, and alcohol breathalyzer. In the event of an unexplained clinically noteworthy abnormal laboratory test value in urine pregnancy test, the test was repeated immediately and followed up until it returned to the normal range and / or an adequate explanation of the abnormality was found.6.1.5.11.5 Pregnancy Testing

[0177] For all participants, pregnancy testing occurred by assessment of serum beta-human chorionic gonadotropin at Screening and Day 28, and urine beta-human chorionic gonadotropin at Day 0 prior to dosing. For participants with a positive pregnancy test at Screening, 1 re-screen was allowed.6.1.5.12 Other Assessments6.1.5.12.1 Mystical Experience Questionnaire

[0178] The 4-item Mystical Experience Questionnaire (MEQ-4) is a brief, validated version of the 30-item MEQ validated patient-reported questionnaire which assesses an individual episode of a mystical experience produced by classic hallucinogens. The MEQ-4 uses 4 questions across 4 areas of experience:• Mystical (including items concerning internal unity, external unity, noetic quality, and sacredness)46 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)• Positive mood• Transcendence of time and space• Ineffability

[0179] Patients were asked to rate each item of the MEQ-4 on a 6-point scale.6.1.5.12.2 Challenging Experience Questionnaire

[0180] The Challenging Experience Questionnaire (CEQ-7) is a validated, brief version of the 26-item CEQ patient-reported measure which assesses 7 dimensions of psychedelic-occasioned challenging experiences: grief, fear, death, insanity, isolation, physical distress, and paranoia. Responses were rated on a 6-point scale (0: None / not at all, 1: So slight cannot decide, 2: Slight, 3: Moderate, 4: Strong; 5: Extreme [more than ever before in my life]) to indicate the degree of subjective effects during the dosing session. Total CEQ score was expressed as the percentage of the total possible ratings on the scale.6.1.5.12.3 Blinding Assessment

[0181] The adequacy of the blind was determined by asking the patient and blinded efficacy rater at the end of the study to assess which treatment the patient received, scored on a 5-point Likert scale:1. I am positive I received the higher dose of study drug.2. I think I received the higher dose of study drug.3. I cannot tell whether I received the higher dose of study drug.4. I think I received the lower dose of study drug.5. I am positive I received the lower dose of study drug.6.1.5.12.4 Suicidal Ideation and Behavior Risk Monitoring

[0182] Patients were monitored appropriately and were observed closely for suicidal ideation and behavior or any other unusual changes in behavior. Patients who experienced signs of suicidal ideation or behavior underwent a risk assessment.

[0183] When informed consent was given, families and caregivers of patients being treated were alerted to the need to monitor patients 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.47 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0184] Baseline assessment of suicidal ideation and behavior was monitored during the Follow-Up Period using the Columbia-Suicide Severity Rating Scale (C-SSRS). The “baseline / screening” version was administered at Screening and Day -1 (since the purpose of application at these time points was to exclude patients with suicidal ideation prior to dosing), and the “since last visit” version was administered thereafter (since the purpose of the application at these timepoints was to monitor patients after dosing had started).

[0185] The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and behavior. Suicidal ideation was classified on a 5-item scale. The C- SSRS also captured 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 captured 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 was classified for the initial, most lethal, and most recent attempts.6.1.5.12.5 Monitoring for Psychosis

[0186] Patients were monitored for the presence of psychosis after the dosing session during the Follow-Up Period using the BPRS+. The BPRS+ is a 4-item, clinician-administered subscale of the 18-item BPRS, used to assess symptoms of psychosis, anxiety, and depression. The 4-item positive symptom subscale assessed 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. Participants were monitored for the presence of psychosis after the dosing session during the Follow-up Period using the BPRS+. A score of 0 was recorded if the symptom was not assessed.6.1.5.12.6 Assessment of Injection Site Reactions

[0187] Following administration of the study drug, the location of the SC injection was evaluated to determine whether there were any local changes to the area surrounding the injection site per the SoA. If findings were observed, a detailed description of the events was included in the source documentation, and an appropriate AE term was included in the case report form.48 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.5.12.7 Discharge Readiness Assessment

[0188] The post-dose discharge readiness evaluation was a clinical examination that included an assessment of the patient’s psychiatric and physical status and associated health parameters, including vital signs and the status of any treatment-emergent AEs. The discharge readiness review was performed hourly between the 4-hour and 8-hour post-dose timepoint, and per the SoA.

[0189] At the time of the 8-hour assessment and prior to discharge, patients were required to 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, 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 of involuntary movements, and / or sweating), were required to be resolved or stable and not clinically significant at the time of discharge.

[0190] The patient was not discharged prior to 8 hours post-dose (regardless of prior documented “readiness”). If the patient’s clinical condition did not warrant discharge at the 8-hour post-dose timepoint, the patient was managed under standard of care until ready for discharge and confirmed by a medically qualified Investigator.6.1.6. Adverse Events, Serious Adverse Events, and Other Safety Reporting

[0191] An AE is any untoward medical occurrence in a clinical study patient, 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.

[0192] All AEs that occurred after the participant provided informed consent and up to30 calendar days after the last study visit, were recorded. AEs were recorded each time the participant was seen or contacted by the Investigator or the study staff.

[0193] All AEs were graded for severity using the terms mild, moderate, or severe. When changes in the severity of an AE occurred more frequently than once a day, the maximum49 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)severity for the experience was noted. If the severity category changed over several days, those changes were recorded as separate AEs.

[0194] Each AE (serious or non-serious) was assessed by the Investigator as related, possibly related or not related to the study drug.

[0195] An adverse event of special interest (AESI) was defined as an event of scientific and medical concern specific to the study drug, for which rapid communication and ongoing monitoring were warranted. In this study, the AESIs included psychiatric events requiring medical intervention and potential seizure-related activity.

[0196] All AEs and SAEs were followed by the study staff until resolution, stabilization, or the participant was lost to follow-up.

[0197] An AE or suspected adverse reaction was considered “serious” if, in the view of either the Investigator or Sponsor, it resulted in any of the following outcomes:• Death (death was 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 did not include an AE that, had it occurred in a more serious form, might have caused death)• Persistent or significant disability / incapacitation• Inpatient hospitalization or prolongation of existing hospitalization• Congenital anomaly / birth defect6.1.7. Data Quality Assurance

[0198] Quality management for the study was conducted using a risk-based approach in compliance with FDA regulations and ICH E6(R2) GCP principles with the overall objective to ensure the protection of trial participants, the reliability and integrity of clinical data, and compliance with regulatory requirements throughout the study.

[0199] Oversight activities focused on subject safety, accurate assessment of efficacy endpoints, and data integrity. Monitoring, safety review, issue management, independent audits, and quality controls were implemented to ensure the reliability of the data presented in this report.50 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.8. Study Participants Results Summary

[0200] Overall, 84 participants were randomized in the study (41 and 43 in the 30 mg and 1.5 mg groups, respectively). Demographics and baseline characteristics of the participants in both the 1.5 mg group versus the 30 mg group are shown below in (Table 5).Table 5. Demographics and Baseline Characteristics (Safety Analysis Set)Compound 1 Compound 1 Overall30 1,1" 1-5 mg (N=84) (N=41) (N=43)Race, n (%)aWhite 24 (58.5) 27 (62.8) 51 (60.7) Black or African American 12 (29.3) 11 (25.6) 23 (27.4) Asian 1 (2.4) 2 (4.7) 3 (3.6) American Indian or Alaska Native 0 1 (2.3) 1 (1.2) Native Hawaiian or Other Pacific Islander 2 (4.9) 0 2 (2.4) Other 1 (2.4) 2 (4.7) 3 (3.6) Multiple 1 (2.4) 0 1 (1.2) Ethnicity, n (%)Hispanic or Latino 13 (31.7) 7 (16.3) 20 (23.8) Not Hispanic or Latino 28 (68.3) 36 (83.7) 64 (76.2) Median age. years 34.0 31.0 33.0 Mean Height, cm (SD) 163.6 (8.58) 164.5 (6.22) 164.1 (7.43) Mean Weight, kg (SD) 85.57 (27.213) 91.95 (25.366) 88.84 (26.320) Mean Body Mass Index, kg / m2(SD) 31.89 (9.475) 33.98 (9.156) 32.96 (9.316) Abbreviations N = total number of participants per treatment group and overall: n = number of participants in each category: SD = standard deviation.a. Percentages are based on the number of participants in the Safety Analysis Set with available data by treatment group and overall.

[0201] Most participants completed the study (92.9% participants) with a slightly higher completion rate in the 30 mg group (97.6% participants) versus the 1.5 mg group (88.4% participants) (FIG.3). Six (7.1%) participants withdrew early, primarily being lost to follow-up. No treatment-emergent deaths or TEAEs led to withdrawal of participants from the study. All participants received a single dose of the study drug, with consistent exposure across groups.51 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0202] Important protocol deviations occurred at similar rates in both groups (63.4% in the 30 mg group and 60.5% in the 1.5 mg group), with the most frequent deviations involving the use of incorrect versions of ICFs and incorrect lookback periods on the MADRS.

[0203] Baseline disease characteristics were generally balanced between groups (Table 6). Overall, most participants experienced moderate-to-severe PPD, as indicated by the mean baseline HAMD-17 and MADRS scores of 27.5 and 33.3, respectively. The average duration of PPD was 7.32 months. Most participants had no prior PPD episodes (70.2%) and were not on medication for their current episode (84.5%). Overall, of the 10 participants (11.9% of all participants) undergoing concomitant psychotherapy, 8 participants were in the 30 mg group (19.5%) and 2 in the 1.5 mg group (4.7%). Additionally, 90.5% had no prior experience with hallucinogenic agents.Table 6. Disease History (Safety Analysis Set)Compound 1 Compound 130 mg 1.5 mg Overall Parameter Statistic (N=41) (N=43) (N=84) Duration of PPD (months) n 41 43 84Mean (SD) 7.64 (3.866) 7.02 (3.449) 7.32 (3.650) Median 6.64 6.90 6.70 Min, Max 1.7, 17.7 1.5, 13.9 1.5, 17.7 Onset of PPD n 41 43 84 Postpartum n(%) 26 (63.4) 24 (55.8) 50 (59.5) Antenatal n (%) 15 (36.6) 19 (44.2) 34 (40.5) Time since birth (months) n 41 43 84Mean (SD) 6.80 (3.636) 6.46 (3.480) 6.63 (3.539) Median 6.34 6.18 6.32 Min, Max 1.3, 14.8 1.2, 13.9 1.2, 14.8 Any prior PPD episodes n 41 43 84No n (%) 28 (68.3) 31 (72.1) 59 (70.2) Yes n (%) 13 (31.7) 12 (27.9) 25 (29.8) Were medications taken to treat current n 41 43 84 episode of PPD?No n (%) 34 (82.9) 37 (86.0) 71 (84.5) Yes n (%) 7 (17.1) 6 (14.0) 13 (15.5) Prior hallucinogenic agent experience n 41 43 8452 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 130 mg 1.5 mg Overall Parameter Statistic (N=41) (N=43) (N=84) No n (%) 37 (90.2) 39 (90.7) 76 (90.5) Yes n (%) 4 (9.8) 4 (9.3) 8 (9.5) Baseline HAMD-17 total score n 41 43 84Mean (SD) 27.5 (2.52) 27.6 (2.62) 27.5 (2.56) Median 27.0 28.0 27.5 Min, Max 23, 32 24, 32 23, 32 Baseline MADRS total score n 41 43 84Mean (SD) 33.4 (6.90) 33.2 (5.00) 33.3 (5.97) Median 34.0 34.0 34.0 Min, Max 15, 47 20, 41 15, 47 Baseline MADRS total score categories n 41 43 84<30 n (%)a11 (26.8) 11 (25.6) 22 (26.2) >30 n (%) 30 (73.2) 32 (74.4) 62 (73.8) SSRI Use n 41 43 84Non-Usersbn (%) 35 (85.4) 39 (90.7) 74 (88.1) Concomitant SSRI Usecn (%) 6 (14.6) 4 (9.3) 10 (11.9) Stable Usersdn (%) 5 (12.2) 4 (9.3) 9 (10.7) New Usersen (%) 0 0 0 Stopping Usersfn (%) 1 (2.4) 0 1 (1.2) Concomitant Psychotherapy n 41 43 84Yes n (%) 8 (19.5) 2 (4.7) 10 (11.9) No n (%) 33 (80.5) 41 (95.3) 74 (88.1) Abbreviations: HAMD-17 = Hamilton Rating Scale for Depression; MADRS = Montgomery -Asberg Depression Rating Scale; Max = maximum; Min = minimum; n = number of participants; N = total number of participants per treatment group and overall; n = number of participants reporting; PPD = postpartum depression; SD = Standard Deviation; SSRI = selective serotonin reuptake inhibitors.a. Percentages are based on the number of participants in the Safety Analysis Set with available data by treatment group and overall.b. ‘Non-users’ were participants that never took any SSRI before or during the study.c. ‘Concomitant Users’: Stable Users + New Users + Stopping Users.d. ‘Stable users' were participants that took SSRIs prior to Screening and continued throughout the study. e. ‘New users’ were participants that started taking SSRIs after dosing with the study drug (and took none before). f. ‘Stopping users’ were participants that were taking SSRIs at the time of dosing but had stopped before completing the study.

[0204] Overall medical history was reported by 92.9% of participants and was well balanced between groups, with major depression and perinatal depression being the most common53 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)conditions (each reported by 29.8%), followed by cesarean section (17.9%). Ongoing medical history was reported by 94.0% of participants, with obesity (31.0%), drug hypersensitivity (25.0%), and seasonal allergies (17.9%) being the most common.

[0205] Prior medications were reported by 59.5% of participants overall, the most common being sertraline (9.5%), escitalopram oxalate (8.3%), and paracetamol (7.1%). Most participants (85.7%) reported concomitant medications, the most common being paracetamol (25.0%), ibuprofen (17.9%), and vitamins (16.7%). These were well balanced across groups.6.1.9. Efficacy Results6.1.9.1 Primary Efficacy Endpoint

[0206] The primary efficacy endpoint was the change from Baseline to Day 7 in MADRS total score, with a decrease in score representing improvement in depression severity.

[0207] The primary efficacy endpoint was met. Compound 1 showed a statistically significant greater decrease from Baseline in MADRS total score between the 30 mg and 1.5 mg groups at Day 7, supporting the alternative hypothesis (i.e., the decrease from Baseline in the 30 mg group was larger than that in the 1.5 mg group). At Baseline, the mean (SD) MADRS total score for the 30 mg and 1.5 mg groups was similar (33.41 [6.903] and 33.21 [4.998], respectively). At Day 7, a negative change from Baseline in mean (SD) MADRS total score was observed for both groups (-23.29 [12.639] in the 30 mg group and -17.36 [12.045] in the 1.5 mg group). Model-based analysis showed a least squares mean (LSM) (SE) of -22.99 (1.771) for the 30 mg group versus -17.20 (1.719) for the 1.5 mg group, and an LSM difference (SE) of -5.80 point (2.466) (90% CI: -9.85, -1.74; 1 -sided P = 0.0094) (Table 7).Table 7. Primary Efficacy Endpoint, Change from Baseline in MADRS Total Score to Day 7 (Full Analysis Set)Compound 130 mg Compound 11.5 mg Visit Statistic (N=41) (N=43) Baseline n 41 43Mean (SD) 33.41 (6.903) 33.21 (4.998) Median 34.00 34.00 Min, Max 15.0.47.0 20.0, 41.0 Day 7 n 35 39Mean (SD) 9.97 (9.724) 15.56 (11.912)54 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 130 mg Compound 11.5 mg Visit Statistic (N=41) (N=43)Median 7.00 12.00 Min, Max 1.0, 40.0 0.0, 38.0 Day 7 change from Baseline n 35 39Mean (SD) -23.29 (12.639) -17.36 (12.045) Median -26.00 -19.00 Min, Max -42.0, 10.0 -40.0, 13.0 LSM (SE) -22.99 (1.771) -17.20 (1.719) 90% CI (-25.91, -20.08) (-20.02, -14.37) LSM Difference (SE) -5.80 (2.466)90% CI (-9.85, -1.74)1 -sided p-value 0.0094Abbreviations: CI = confidence interval; FAS = Full Analysis Set: LSM = least squares mean;MADRS = Montgomery-Asberg Depression Rating Scale; MAR = Missing at Random; MMRM = mixed model for repeated measures; MNAR = Missing Not at Random; N = total number of participants per treatment group; n = number of participants reporting; SD = standard deviation; SE = standard error.Missing data due to withdrawal because of lack of efficacy was imputed 1000 times under MNAR whereas all remaining missing data were imputed under a MAR mechanism. The MMRM model includes treatment, visit, treatment by visit interaction, Baseline MADRS total score and an unstructured correlation matrix. The imputed datasets were analyzed using the MMRM model and estimates pooled using Rubin’s roles.

[0208] There were missing MADRS results at Day 7 for a total of 10 participants (6 participants in the 30 mg group and 4 participants in the 1.5 mg group). Missing data were partly due to study discontinuation (1 participant and 2 participants in the 30 mg group and in the 1.5 mg group, respectively), to participants having visits outside of the analysis window (2 participants and 1 participant in the 30 mg group and in the 1.5 mg group, respectively) and to missed visit (1 participant in the 30 mg group). Much of this missing data can be considered a result of the participant population (new mothers) and the demands upon their time, which made it difficult for them to adhere to the study schedule. Of the remaining 3 missing data, 2 were a result of a technical issue / data entry error, and 1 was due to the participant who left before the MADRS assessment was complete.6.1.9.1.1 Sensitivity Analysis of Primary Efficacy Endpoint

[0209] Overall, over half of participants (50 [59.5%] participants; 27 [65.9%] participants in the 30 mg group and 23 [53.5%] participants in the 1.5 mg group) reported prior medications (i.e., medications taken and stopped prior to the dose with the study drug) and 72 [85.7%] participants 55 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)(39 [95.1%] participants in the 30 mg group and 33 [76.7%] participants in the 1.5 mg group) reported concomitant medications (i.e., medications taken on or after the date of the dose of study drug). The most common prior medications included sertraline (2 [4.9%] participants in the 30 mg group and 6 [14.0%] participants in the 1.5 mg group), escitalopram oxalate (6[14.6%] participants in the 30 mg group and 1 [2.3%] participants in the 1.5 mg group), and paracetamol (4 [9.8%] participants in the 30 mg group and 2 [4.7%] participants in the 1.5 mg group). The most common concomitant medications included paracetamol (13 [31.7%] participants in the 30 mg group and 8 [18.6%] participants in the 1.5 mg group), ibuprofen (8 [19.5%] participants in the 30 mg group and 7 [16.3%] participants in the 1.5 mg group), and vitamins not otherwise specified (nos) (9 [22.0%] participants in the 30 mg group and 5[11.6%] participants in the 1.5 mg group)

[0210] Results from both sensitivity analyses — MNAR + MAR imputation (same as primary analysis) and Observed Cases — were consistent with the primary analysis. At Day 7, an LSM difference (SE) of -5.81-point (2.483) (90% CI: -9.89, -1.73; 1-sided P = 0.0096) and -5.62-point (2.469) (90% CI: -10.54, -0.71; 1-sided P = 0.0096) in the 30 mg group versus the 1.5 mg group was reported in the MNAR + MAR imputation and Observed Cases analyses, respectively. These results show a statistically significant change from Baseline in MADRS total score between the 30 mg and 1.5 mg groups at Day 7 and support the alternative hypothesis (i.e., the decrease from Baseline in the 30 mg group was larger than that in the 1.5 mg group).

[0211] The main analysis (MNAR + MAR imputation, hypothetical strategy estimand) also yielded similar results (LSM difference [SE] of -5.80 points [2.466] [90% CI: -9.85, -1.74; 1-sided P = 0.0094]) indicating consistent results across analytical approaches.6.1.9.2 Secondary Efficacy Endpoints6.1.9.2.1 Change from Baseline at Day 1, Day 14, and Day 28 in MADRS Total Score

[0212] Beyond the significant reduction in the change from Baseline in the MADRS total scores at Day 7 in the 30 mg group, the changes from Baseline in MADRS total score at Day 14 also demonstrated a substantial reduction in favor of 30 mg, with an LSM difference (SE) of -4.23 points (2.432) (90% CI: 8.23, 0.23). The reduction in the MADRS total scores from Baseline remained constant in the 30 mg group from Day 1 to Day 28, ranging from a maximum of -24.1256 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)(Day 14) to a minimum of -22.99 (Day 7), with a stronger treatment effect in the 30 mg group versus the 1.5 mg group, as shown by statistically significant LSM differences (SE) in favor of the 30 mg group (Table 8).Table 8. Secondary Efficacy Endpoint, Change from Baseline in MADRS Total Score at Day 1, 14, and 28 (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline n 41 43Mean (SD) 33.41 (6.903) 33.21 (4.998) Median 34.00 34.00 Min, Max 15.0, 47.0 20.0, 41.0 Day 1 n 41 42Mean (SD) 9.88 (8.978) 13.64 (11.716) Median 6.00 11.00 Min, Max 0.0, 40.0 0.0, 44.0 Day 1 change from Baseline n 41 42Mean (SD) -23.54 (11.634) -19.48 (11.532) Median -28.00 -22.50 Min, Max -40.0, 19.0 -40.0, 11.0 LSM (SE) -23.45 (1.632) -19.77 (1.603) 90% CI (-26.13, -20.76) (-22.40, -17.13) LSM Difference (SE) -3.68 (2.287)90% CI (-7.44, 0.08)1 -sided p-value 0.0538Day 14 n 38 36Mean (SD) 9.03 (10.484) 12.44 (10.919) Median 5.00 10.50 Min, Max 0.0. 40.0 0.0, 43.0 Day 14 change from Baseline n 38 36Mean (SD) -24.79 (12.390) -20.47 (10.888) Median -26.50 -22.00 Min, Max -43.0, 5.0 -40.0.4.0 LSM (SE) -24.12 (1.719) -19.88 (1.721) 90% CI (-26.95, -21.29) (-22.72, -17.05) LSM Difference (SE) -4.23 (2.432)57 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43)90% CI (-8.23, -0.23)1 -sided p-value 0.0408Day 28 n 39 36Mean (SD) 9.51 (11.749) 12.19 (12.021) Median 5.00 6.50 Min, Max 0.0, 46.0 0.0, 40.0 Day 28 change from Baseline n 39 36Mean (SD) -23.90 (14.151) -20.36 (11.296) Median -26.00 -20.50 Min, Max -45.0, 6.0 -40.0, 4.0 LSM (SE) -23.81 (1.847) -21.01 (1.868) 90% CI (-26.85, -20.77) (-24.08, -17.94) LSM Difference (SE) -2.80 (2.628)90% CI (-7.12, 1.52)1 -sided p-value 0.1434Abbreviations: CI = confidence interval; FAS = Full Analysis Set; LSM = least squares mean;MADRS = Montgomery-Asberg Depression Rating Scale; MAR = Missing at Random; MMRM = mixed model for repeated measures; MNAR = Missing Not at Random; N = total number of participants per treatment group; n = number of participants reporting; SD = standard deviation; SE = standard error.Missing data due to withdrawal because of lack of efficacy was imputed 1000 times under MNAR whereas all remaining missing data were imputed under a MAR mechanism. The MMRM model includes treatment, visit, treatment by visit interaction, Baseline MADRS total score and an unstructured correlation matrix. The imputed datasets were analyzed using the MMRM model and estimates pooled using Rubin's rules.

[0213] Improvements in MADRS total scores and corresponding changes from Baseline for compound 1 were sustained through Day 28, with a greater treatment effect observed in the 30 mg group versus the 1.5 mg group (FIGs. 4A-4B).6.1.9.2.2 Percentage of Participants With MADRS Response (>50% Reduction in Score from Baseline) at Day 7

[0214] At Day 7, a total of 77.14% of participants in the 30 mg group and 61.54% participants in the 1.5 mg group were considered treatment responders (i.e., had a >50% reduction in MADRS total score from Baseline) (Table 9). Across timepoints, the observed difference in response rate supports the primary efficacy findings that treatment effect was persistent over the course of the study and was stronger in the 30 mg group compared to the 1.5 mg group.58 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 9. Secondary Efficacy Endpoint, Proportion of MADRS Responders (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Day 1 Responders3n / n* (%) 33 / 41 (80.49) 28 / 42 (66.67)90% CI (70.31, 90.67) (54.70, 78.63) Difference in MADRS Response Rate 13.8290% CI (-1.89, 29.53)Day 7 Responders n / n* (%) 27 / 35 (77.14) 24 / 39 (61.54)90% CI (65.47, 88.82) (48.72, 74.35) Difference in MADRS Response Rate 15.6090% CI (-1.73, 32.94)Day 14 Responders n / n* (%) 31 / 38 (81.58) 25 / 36 (69.44)90% CI (71.24, 91.92) (56.82, 82.07) Difference in MADRS Response Rate 12.1390% CI (-4.19, 28.46)Day 28 Responders n / n* (%) 28 / 39 (71.79) 25 / 36 (69.44)90% CI (59.94, 83.65) (56.82, 82.07) Difference in MADRS Response Rate 2.3590% CI (-14.97, 19.67)Abbreviations: CI = confidence interval; MADRS = Montgomery-Asberg Depression Rating Scale; N = total number of participants per treatment group; n = number of MADRS responders; n* = number of participants with available MADRS total score.a. A responder is a participant with a >50% reduction in Baseline MADRS total score at a specified visit. Cis for the proportion of responders and their difference between treatment groups are obtained as Wald-like intervals based on the Normal approximation.6.1.9.2.3 Percentage of Participants With MADRS Remission (Score <10) at Day 7

[0215] At Day 7, a total of 71.43% of participants in the 30 mg group and 41.03% participants in the 1.5 mg group were considered remitters (i.e., had a MADRS score of <10) with a difference in MADRS remission rate of 30.40% (Table 10). The 90% CI at Day 7 excludes zero, as does the CI at Day 14. Across timepoints, the observed difference in remission rate supports the primary efficacy findings that the treatment effect was persistent over the course of the study and was stronger in the 30 mg group versus the 1.5 mg group.59 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 10. Secondary Efficacy Endpoint, Proportion of MADRS Remitters (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline Score <10 n / n* (%) 0 / 41 (0.00) 0 / 43 (0.00) Day 1 Remitters3n / n* (%) 26 / 41 (63.41) 20 / 42 (47.62)90% CI (51.04. 75.79) (34.94, 60.29) Difference in MADRS Remission Rate 15.8090% CI (-1.92.33.51)Day 7 Remitters n / n* (%) 25 / 35 (71.43) 16 / 39 (41.03)90% CI (58.87. 83.99) (28.07, 53.98) Difference in MADRS Remission Rate 30.4090% CI (12.36. 48.45)Day 14 Remitters n / n* (%) 27 / 38 (71.05) 18 / 36 (50.00)90% CI (58.95. 83.15) (36.29, 63.71) Difference in MADRS Remission Rate 21.0590% CI (2.77, 39.34)Day 28 Remitters n / n* (%) 27 / 39 (69.23) 19 / 36 (52.78)90% CI (57.07. 81.39) (39.09, 66.46) Difference in MADRS Remission Rate 16.4590% CI (-1.85. 34.76)Abbreviations: CI = confidence interval; MADRS = Montgomery -Asberg Depression Rating Scale; N = total number of participants per treatment group; n = number of MADRS remitters; n* = number of participants with available MADRS total score.A remitter was a participant with a MADRS total score <10 at a specified visit. Cis for the proportion of remitters and their difference between treatment groups were obtained as Wald-like intervals based on the Normal approximation.6.1.9.2.4 CGI-I at Day 1, Day 7, and Day 28

[0216] At Day 1, in the 30 mg group, 26 (63.4%) participants and in the 1.5 mg group, 21 (50.0%) participants were considered CGI-I responders (i.e., had a score of ‘Much Improved’ or ‘Very Much Improved’). The difference in CGI-I response rate between groups was 13.41 (90% CI for difference: -4.31, 31.14).

[0217] At Day 7, in the 30 mg group 29 (76.3%) participants and in the 1.5 mg group 24 (60.0%) participants were considered CGI-I responders. The difference in CGI-I response rate between groups was 16.32 (90% CI for difference: -0.74; 33.38).60 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0218] At Day 28, in the 30 mg group 28 (71.8%) participants and in the 1.5 mg group 27 (73.0%) participants were considered CGI-I responders. The difference in CGI-I response rate between groups was -1.18 (90% CI for difference: -18.05, 15.69) (Table 11).Table 11. Secondary Efficacy Endpoint, Clinical Global Impression - Improvement (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) DayI n 41 42 Much / Vcry Much Improved n (%)a26 (63.4) 21 (50.0) Very Much Improved n (%) 10 (24.4) 6 (14.3) Much Improved n (%) 16 (39.0) 15 (35.7) Minimally Improved n (%) 11 (26.8) 12 (28.6) No Change or Worse n (%) 4 (9.8) 9 (21.4) No Change n (%) 4 (9.8) 7 (16.7) Minimally Worse n (%) 0 2 (4.8) Much Worse n (%) 0 0 Very7Much Worse n (%) 0 0 CGI-I Responsebn (%) 26 (63.41) 21 (50.00)90% CI (51.04, 75.79) (37.31, 62.69) Difference in CGI-I Response Rate 13.4190% CIc(-4.31, 31.14)Day 7 n 38 40 uch / Ven Much Improved n (%) 29 (76.3) 24 (60.0) Very Much Improved n (%) 14 (36.8) 11 (27.5) Much Improved n (%) 15 (39.5) 13 (32.5) Minimally Improved n (%) 5 (13.2) 6 (15.0) No Change or Worse n (%) 4 (10.5) 10 (25.0) No Change n (%) 4 (10.5) 9 (22.5) Minimally Worse n (%) 0 1 (2.5) Much Worse n (%) 0 0 Very Much Worse n (%) 0 0 CGI-I Response* n (%) 29 (76.32) 24 (60.00)90% CI (64.97, 87.66) (47.26, 72.74) Difference in CGI-I Response Rate 16.3290% CI (-0.74, 33.38)Day 28 n 39 37 Much / Vcry Much Improved n (%) 28 (71.8) 27 (73.0) Very Much Improved n (%) 18 (46.2) 13 (35.1) Much Improved n (%) 10 (25.6) 14 (37.8)61 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Minimally Improved n (%) 5 (12.8) 2 (5.4) No Change or Worse n (%) 6 (15.4) 8 (21.6) No Change n (%) 5 (12.8) 7 (18.9) Minimally Worse n (%) 1 (2.6) 1 (2.7) Much Worse n (%) 0 0 Very Much Worse n (%) 0 0 CGI-I Response* n (%) 28 (71.79) 27 (72.97)90% CI (59.94, 83.65) (60.96, 84.98) Difference in CGI-I Response Rate -1.1890% CI (-18.05, 15.69)Abbreviations: CGI-I = Clinical Global Impression - Improvement; CI = confidence interval; N = total number of participants per treatment group; n = number of participants reporting.a. Percentages are based on the number of participants in the Full Analysis Set with available data by treatment group.b. A CGI-I responder is a participant responding with ‘Much Improved’ or ‘Very Much Improved’.c. Cis for the proportion of responders and their difference betw een treatment groups are obtained as Wald-like intervals based on tire Normal approximation.6.1.9.2.5 CGI-S at Day 1, Day 7, and Day 28

[0219] At Baseline, the majority of participants in the 30 mg group were rated ‘Moderately ill’ (22 [53.7%] participants), with no participants with less severe illness; whereas the majority of participants in the 1.5 mg group were ‘Markedly ill’ (29 [67.4%] participants), with only 9 (20.9%) participants with less severe illness (all ‘Moderately ill’).

[0220] By Day 1, the 30 mg group showed a shift toward less severe illness, with6 (14.6%) participants achieving a score of ‘Normal, not ill at all’. Similarly, by Day 1, the 1.5 mg group showed a shift toward less severe illness, with 3 (7.1%) participants achieving a score of ‘Normal, not ill at all’. There were marked differences between groups in the percentage of participants considered ‘Moderately ill’ at Day 1, with 7 (17.1%) of participants in the 30 mg group compared to 18 (42.9%) of participants in the 1.5 mg group.

[0221] By Day 7, 7 (18.4%) participants in the 30 mg group and 5 (12.5%) participants in the 1.5 mg group achieved the score of ‘Normal, not ill at all’. More participants in the 1.5 mg group remained ‘Moderately ill’ compared to participants in the 30 mg group, 9 (22.5%) and 4 (10.5%), respectively.62 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0222] By Day 28, 16 (41.0%) participants in the 30 mg group and 10 (27.0%) participants in the 1.5 mg group achieved the score of ‘Normal, not ill at all’ (Table 12). Other severity categories were similar between groups at Day 28.Table 12. Secondary Efficacy Endpoint, Clinical Global Impression - Severity (Full Analysis Set)Compound 1 30 mg Compound 1 1.5 mg Visit Statistic (N=41) (N=43) Baseline n 41 43 Normal, not ill at all n (%)a0 0 Borderline ill n (%) 0 0 Mildly ill n (%) 0 0 Moderately ill n (%) 22 (53.7) 9 (20.9) Markedly ill n (%) 19 (46.3) 29 (67.4) Severely ill n (%) 0 5 (11.6) Among the most extremely ill patients n (%) 0 0 Day 1 n 41 42 Normal, not ill at all n (%) 6 (14.6) 3 (7.1) Borderline ill n (%) 10 (24.4) 6 (14.3) Mildly ill n (%) 16 (39.0) 9 (21.4) Moderately ill n (%) 7 (17.1) 18 (42.9) Markedly ill n (%) 2 (4.9) 4 (9.5) Severely ill n (%) 0 2 (4.8) Among the most extremely ill patients n (%) 0 0 Day 7 n 38 40 Normal, not ill at all n (%) 7 (18.4) 5 (12.5) Borderline ill n (%) 12 (31.6) 9 (22.5) Mildly ill n (%) 13 (34.2) 10 (25.0) Moderately ill n (%) 4 (10.5) 9 (22.5) Markedly ill n (%) 2 (5.3) 7 (17.5) Severely ill n (%) 0 0 Among the most extremely ill patients n (%) 0 0 Day 28 n 39 37 Normal, not ill at all n (%) 16 (41.0) 10 (27.0) Borderline ill n (%) 6 (15.4) 8 (21.6) Mildly ill n (%) 8 (20.5) 8 (21.6) Moderately ill n (%) 6 (15.4) 5 (13.5) Markedly ill n (%) 3 (7.7) 5 (13.5) Severely ill n (%) 0 1 (2.7) Among the most extremely ill patients n (%) 0 0 N = total number of participants per treatment group: n = number of participants reporting.63 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)a. Percentages are based on the number of participants in the Full Analysis Set with available data by treatment group.6.1.9.2.6 Changes from Baseline in HAM -A Total Score at Day 7

[0223] The medians of HAM- A total score (20.00 [min 13.0, max 40.0] and 22.00 [min 9.0, max 41.0] in the 30 mg and 1.5 mg group, respectively) at Baseline showed that more participants had mild or mild-to-moderate anxiety compared to moderate-to-severe anxiety. Based on an MMRM model, there was a reduction in HAM-A total score from Baseline to Day 7 in the 30 mg group (LSM [SE] change: -10.59 [1.154]; 90% CI: -12.88, -8.29) and the 1.5 mg group (LSM [SE] change: -9.58 [1.117]; 90% CI: -11.81, -7.36), and the LSM difference [SE] between groups was -1.01 [1.607] (90% CI for difference: -4.20, 2.19; 1-sided p-value = 0.2665) (Table 13). Both groups improved at all other timepoints, but differences between groups on the change in HAM-A from Baseline were not significant.Table 13. Secondary Efficacy Endpoint, Hamilton Anxiety Scale (Full Analysis Set)aCompound 130 mg Compound 11.5 mg Visit Statistic (N=41) (N=43) Baseline n 40 43Mean (SD) 21.75 (6.275) 21.14 (7.130) Median 20.00 22.00 Min. Max 13.0.40.0 9.0.41.0 Day 7 n 36 38Mean (SD) 10.31 (6.886) 11.13 (8.656) Median 9.00 8.50 Min. Max 2.0, 31.0 1.0. 33.0 Day 7 change from Baseline n 35 38Mean (SD) -11.09 (8.699) -9.37 (6.764) Median -12.00 -8.00 Min. Max -29.0. 10.0 -26.0, 1.0 LSM (SE) -10.59 (1.154) -9.58 (1.117) 90% CI (-12.88. -8.29) (-11.81, -7.36) LSM Difference (SE) -1.01 (1.607)90% CI (-4.20.2.19)1 -sided p-value 0.266564 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Abbreviations: CI = confidence interval; LSM = least squares mean; MMRM = Mixed Model for Repeated Measures; N = total number of participants per treatment group; n = number of participants reporting;SD = Standard Deviation; SE = standard error.a. The MMRM model includes treatment, visit, treatment by visit interaction, Baseline H AM-A score and an unstructured correlation matrix.

[0224] At Day 7, 23 (65.71%) participants in the 30 mg group and 20 (52.63%) participants in the 1.5 mg group were considered responders (Table 14). There was no significant difference between groups in HAM-A response rate at Day 7 (13.08; 90% CI: -9.04, 27.36) or at any other timepoint.Table 14. Secondary Efficacy Endpoint, Proportion of HAM-A Responders (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Day 1 Responders3n / n* (%) 6 / 40 (15.00) 12 / 41 (29.27)90% CIb(5.71, 24.29) (17.58, 40.96) Difference in HAM-A Response Rate -14.2790% CI (-29.20, 0.66)Day 7 Responders n / n* (%) 23 / 35 (65.71) 20 / 38 (52.63)90% CI (52.52, 78.91) (39.31, 65.95) Difference in HAM-A Response Rate 13.0890% CI (-5.67, 31.84)Day 14 Responders n / n* (%) 26 / 37 (70.27) 22 / 36 (61.11)90% CI (57.91, 82.63) (47.75, 74.48) Difference in HAM-A Response Rate 9.1690% CI (-9.04, 27.36)Day 28 Responders n / n* (%) 27 / 39 (69.23) 25 / 36 (69.44)90% CI (57.07, 81.39) (56.82, 82.07) Difference in HAM-A Response Rate -0.2190% CI (-17.74. 17.31) Abbreviations: CI = confidence interval; HAM-A = Hamilton Anxiety Scale; N = total number of participants per treatment group;n = number of HAM-A responders; n* = number of participants with available HAM-A total score. a. A responder is a participant with a >50% reduction in Baseline HAM-A total score at a specified visit. b. Cis for the proportion of responders and their difference between treatment groups are obtained as Wald-like intervals based on tire Normal approximation.65 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0225] Concerning the proportion of HAM-A remitters, at Day 1 there was a difference in favor of 1.5 mg group (-17.07; CI:-29.06, -5.09); however, this trend did not continue at other timepoints at Day 7, 11 (30.56%) participants in the 30 mg group and 13 (34.21%) participants in the 1.5 mg group were considered remitters (Table 15). The difference between groups in HAM-A remission rate at Day 7 was -3.65 (90% CI: -21.54, 14.23).Table 15. Secondary Efficacy Endpoint, Proportion of HAM-A Remitters (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline Score < 7 n / n* (%) 0 / 40 (0.00) 0 / 43 (0.00) Day 1 Remitters3n / n* (%) 2 / 41 (4.88) 9 / 41 (21.95)90% CIb(0.00, 10.41) (11.32, 32.58) Difference in HAM-A Remission Rate -17.0790% CI (-29.06, -5.09)Day 7 Remitters n / n* (%) 11 / 36 (30.56) 13 / 38 (34.21)90% CI (17.93, 43.18) (21.55, 46.87) Difference in HAM-A Remission Rate -3.6590% CI (-21.54, 14.23)Day 14 Remitters n / n* (%) 20 / 38 (52.63) 20 / 36 (55.56)90% CI (39.31, 65.95) (41.93, 69.18) Difference in HAM-A Remission Rate -2.9290% CI (-21.98, 16.13)Day 28 Remitters n / n* (%) 18 / 40 (45.00) 18 / 36 (50.00)90% CI (32.06, 57.94) (36.29, 63.71) Difference in HAM-A Remission Rate -5.0090% CI (-23.85, 13.85) Abbreviations: CI = confidence interval; HAM-A = Hamilton Anxiety Scale; N = total number of participants per treatment group; n = number of HAM-A responders; n* = number of participants with available HAM-A total score. a. A remitter is a participant with a HAM-A total score < 7 at a specified visit.b. Cis for the proportion of remitters and their difference between treatment groups are obtained as Wald-like intervals based on the Nomral approximation.6.1.9.3 Other Efficacy Endpoints6.1.9.3.1 MEQ-4

[0226] The percentage of participants reporting a moderate, strong, or extreme response was generally higher in the 30 mg group compared with the 1.5 mg group for the following MEQ-466 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)items: mystical (sense of oneness, insight into ultimate reality, or sacredness), transcendence of time and space, and ineffability. This trend is reflected in the MEQ-4 total scores, with mean (SD) / median values of 3.213 (1.3493 ) / 3.500 and 1.733 (1.2433) / 1.500 for the 30 mg and the 1.5 mg groups, respectively (Table 16), indicating a more pronounced mystical experience in participants receiving 30 mg. The only item for which the 2 groups reported comparable percentages of moderate or higher responses was positive mood.Table 16. Summary of Mystical Experience Questionnaire (Full Analysis Set)Item Compound 1 30 mg Compound 1 1.5 mg Response Statistic (N=41) (N=43) Sense of oneness, insight into ultimate reality, orn41 43 sacrednessNone / Not at all n (%)a7 (17.1) 23 (53.5) So slight cannot deciden(%) 3 (7.3) 4 (9.3) Slightn(%) 4 (9.8) 4 (9.3) Moderate n (%) 4 (9.8) 5 (11.6) Strong n (%) 10 (24.4) 6 (14.0) Extreme n (%) 13 (31.7) 1 (2.3) Positive moodn41 43 None / Not at alln(%) 0 3 (7.0) So slight cannot deciden(%) 1 (2.4) 1 (2.3) Slight n (%) 6 (14.6) 10 (23.3) Moderate n (%) 11 (26.8) 12 (27.9) Strong n (%) 16 (39.0) 14 (32.6) Extreme n (%) 7 (17.1) 3 (7.0) Transcendence of time and spacen41 43 None / Not at all n (%) 5 (12.2) 16 (37.2) So slight cannot deciden(%) 2 (4.9) 10 (23.3) Slight n (%) 10 (24.4) 7 (16.3) Moderate n (%) 3 (7.3) 3 (7.0) Strong n (%) 7 (17.1) 5 (11.6) Extremen(%) 14 (34.1) 2 (4.7) Ineffability (i.e., incapable of being expressed orn41 43 described in words)None / Not at all n (%) 8 (19.5) 22 (51.2) So slight cannot deciden(%) 2 (4.9) 7 (16.3) Slight n (%) 5 (12.2) 4 (9.3) Moderate n (%) 3 (7.3) 6 (14.0) Strongn(%) 11 (26.8) 2 (4.7) Extremen(%) 12 (29.3) 2 (4.7)67 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Item Compound 130 mg Compound 11.5 mg Response Statistic (N=41) (N=43) MEQ-4 Total Score n 41 43Mean (SD) 3.213 (1.3493) 1.733 (1.2433) Median 3.500 1.500 Min, Max 025, 5.00 0.00, 4.50 Abbreviations: N = total number of participants per treatment group; n = number of participants reporting;SD = standard deviation.a. Percentages are based on tire number of participants in the Full Analysis Set with available data by treatment group.6.1.9.3.2 CEQ-7

[0227] Mean (SD) / median CEQ-7 total scores for the 30 mg and the 1.5 mg groups were 19.30 (18.798)714.29 and 9.10 (13,959) / 2.86, respectively (Table 17). Higher scores indicate a more intense challenging experience.Table 17. Summary of Challenging Experience Questionnaire Total Score (Full Analysis Set)Compound 1 Compound 1 Item 30 mg 1.5 mg Statistic (N=41) (N=43) CEQ-7 Total Score n 41 43Mean (SD) 19.30 (18.798) 9.10 (13.959) Median 14.29 2.86 Min, Max 0.0, 80.0 0.0, 54.3 Abbreviations: N = total number of participants per treatment group; n = number of participants reporting; SD = standard deviation.6.1.9.3.3 EPDS

[0228] At Baseline, mean (SD) / median EPDS total scores for the 30 mg and the 1.5 mg group were 20.2 (3.49) / 20.0 and 20.2 (3.74) / 21.0, respectively, indicating likely severe depression. At Day 7, mean (SD) / median EPDS total scores for the 30 mg and the 1.5 mg group were 7.6 (6.20) / 6.0 indicating likely no depression and 9.6 (7.16) / l 0.0 indicating possible mild depression, respectively.

[0229] Changes in mean (SD) / median EPDS total scores from Baseline to Day 7 for the 30 mg and the 1.5 mg group were -12.6 (7.50)7-14.0 and -10.8 (7.04)7-11.5, respectively (Table 18).68 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 18. Summary of Edinburgh Postnatal Depression Scale (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline n 40 42Mean (SD) 20.2 (3.49) 20.2 (3.74) Median 20.0 21.0 Min. Max 14, 26 9, 26 Day 7 n 35 38Mean (SD) 7.6 (6.20) 9.6 (7.16) Median 6.0 10.0 Min. Max 0, 20 0, 27 Day 7 change from Baseline n 35 38Mean (SD) -12.6 (7.50) -10.8 (7.04) Median -14.0 -11.5 Min. Max -25, 1 -23, 1 Day 28 n 37 36Mean (SD) 6.8 (6.10) 8.1 (7.11) Median 5.0 7.0 Min, Max 0, 22 0, 26 Day 28 change from Baseline n 37 36Mean (SD) -13.5 (6.87) -11.9 (7.05) Median -14.0 -11.5 Min, Max -26, 4 -24, 2 Abbreviations: N = total number of participants per treatment group: n = number of participants reporting; SD = standard deviation.6.1.9.3.4 PHQ-9

[0230] At Baseline, mean (SD) / median PHQ-9 total scores for the 30 mg and the 1.5 mg group were 18.6 (3.77)718.0 and 19.6 (4.15) / 21.0, respectively, indicating moderately severe depression. At Day 14, mean (SD) / median PHQ-9 total scores for the 30 mg and the 1.5 mg group were 4.5 (4.89) / 3.0 (none to minimal depression) and 6.5 (6.02) / 5.0 (mild depression), respectively.

[0231] Changes in mean (SD) / median PHQ-9 total scores from Baseline to Day 14 for the 30 mg and the 1.5 mg group were -14.1 (6.27)7-14.5 and -12.9 (6.61)7-14.0, respectively (Table 19).69 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 19. Summary of Patient Health Questionnaire (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline n 41 43Mean (SD) 18.6 (3.77) 19.6 (4.15) Median 18.0 21.0 Min. Max 9, 24 8. 26 Day 14 n 36 35Mean (SD) 4.5 (4.89) 6.5 (6.02) Median 3.0 5.0 Min. Max 0, 19 0, 22 Day 14 change from Baseline n 36 35Mean (SD) -14.1 (6.27) -12.9 (6.61) Median -14.5 -14.0 Min. Max -24, 4 -23, 0 Day 28 n 38 37Mean (SD) 4.6 (5.37) 7.1 (7.18) Median 3.0 5.0 Min. Max 0, 21 0, 25 Day 28 change from Baseline n 38 37Mean (SD) -14.0 (7.15) -12.5 (6.89) Median -15.5 -12.0 Min. Max -24, 3 -24, 1 Abbreviations: N = total number of participants per treatment group: n = number of participants reporting; SD = standard deviation6.1.9.3.5 BIMF

[0232] At Baseline, mean (SD) / median BIMF total scores for the 30 mg and the 1.5 mg group were 65.4 (15.96) / 67.0 and 68.6 (16.22) / 70.0, respectively. At Day 7, mean (SD) / median BIMF total scores for the 30 mg and the 1.5 mg group were 95.8 (14.66) / 95.0 and 87.6 (19.30)89.0, respectively. Lower scores indicate greater impairment in maternal functioning.

[0233] Changes in mean (SD) / median BIMF total scores from Baseline to Day 7 was higher for the 30 mg group (30.7 [19.57] / 29.0) compared to the 1.5 mg group were (18.6 [ 14.71 ] / 20.0) (Table 20).70 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 20. Summary of Barkin Index of Maternal Functioning (Full Analysis Set)Compound 1 Compound 1 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Baseline n 41 43Mean (SD) 65.4 (15.96) 68.6 (16.22) Median 67.0 70.0 Min. Max 28, 97 26, 98 Day 7 n 37 39Mean (SD) 95.8 (14.66) 87.6 (19.30) Median 95.0 89.0 Min. Max 57, 120 39, 120 Day 7 change from Baseline n 37 39Mean (SD) 30.7 (19.57) 18.6 (14.71) Median 29.0 20.0 Min. Max -1, 71 -14, 50 Day 28 n 38 37Mean (SD) 96.8 (14.80) 91.3 (19.13) Median 98.5 97.0 Min, Max 61, 120 40, 120 Day 28 change from Baseline n 38 37Mean (SD) 31.8 (20.59) 23.9 (16.70) Median 33.0 27.0 Min, Max -19, 70 -11, 51 Abbreviations: N = total number of participants per treatment group: n = number of participants reporting; SD = standard deviation.6.1.9.3.6 SF-36

[0234] At Day 28, improvements in the ‘mental health (summary component)’ were observed in both treatment groups, with a mean (SD) score of 47.275 (13.4594) in the 30 mg group and 42.964 (15.7107) in the 1.5 mg group. The greatest increase was seen in the 30 mg group, as reflected by mean (SD) change from Baseline of 28.837 (16.6880) and 23.421 (15.7605) for the 30 mg and the 1.5 mg group, respectively. Among the SF-36 domains the most notable pronounced improvements (change from Baseline of >15) were observed in ‘role limitations due to emotional problems’, ‘vitality’, and ‘social functioning’. Higher scores indicate better health and functioning (Table 21).71 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Table 21. Summary of Short Form 36 Health Survey (SF-36) Domain and Component Scores Change From Baseline to Day 28 (Full Analysis Set)Compound 1 Compound 1 Parameter 30 mg 1.5 mg Visit Statistic (N=41) (N=43) Physical Health (Summary Component)Baseline n 41 43Mean (SD) 59.194 (9.3633) 57.270 (10.0335) Median 60.550 58.540 Min, Max 37.40, 75.53 27.64, 74.64 Day 28 n 38 35Mean (SD) 56.304 (7.3440) 57.507 (7.3617) Median 57.285 57.720 Min, Max 33.89, 70.37 36.01, 73.35 Day 28 change from Baseline n 38 35Mean (SD) -2.461 (8.7834) -0.023 (8.1640) Median -2.070 -1.080 Min, Max -32.67, 21.61 -10.99, 27.06 Mental Health (Summary Component)Baseline n 41 43Mean (SD) 18.621 (9.5720) 19.119 (8.7896) Median 18.180 19.220 Min, Max -2.46, 39.46 0.31, 38.69 Day 28 n 38 36Mean (SD) 47.275 (13.4594) 42.964 (15.7107) Median 50.760 45.060 Min, Max 13.09, 68.97 3.47, 62.25 Day 28 change from Baseline n 38 36Mean (SD) 28.837 (16.6880) 23.421 (15.7605) Median 31.245 24.825 Min, Max -9.36, 58.75 -2.90, 52.09 Physical Functioning (Domain)Baseline n 41 43Mean (SD) 51.752 (7.7917) 50.597 (8.5483) Median 53.710 53.710 Min, Max 25.01, 57.54 23.09, 57.54 Day 28 change from Baseline n 38 3572 Of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 1 Parameter 30 mg 1.5 mg Visit Statistic (N=41) (N=43)Mean (SD) 2.771 (5.3149) 2.679 (6.0545) Median 1.910 1.910 Min, Max -11.48, 19.14 -3.83, 32.53 Role Limitations Due to Physical Health (Domain)Baseline n 41 43Mean (SD) 49.490 (10.9678) 47.026 (10.9953) Median 57.160 50.420 Min, Max 23.47, 57.16 23.47, 57.16 Day 28 change from Baseline n 38 36Mean (SD) 3.428 (10.2809) 6.862 (11.2218) Median 0.000 0.000 Min, Max -31.44, 26.95 -4.49, 33.69 Bodily Pain (Domain)Baseline n 41 43Mean (SD) 50.740 (10.1069) 48.656 (9.1148) Median 50.710 47.480 Min, Max 34.18, 62.00 34.18, 62.00 Day 28 change from Baseline n 38 36Mean (SD) 6.037 (11.8448) 6.642 (7.1904) Median 6.450 6.450 Min, Max -27.82, 23.79 -7.66, 23.79 General HealthBaseline n 41 43Mean (SD) 48.710 (9.0986) 47.923 (10.3715) Median 50.810 46.050 Min, Max 31.79, 65.07 18.95, 66.50 Day 28 change from Baseline n 38 36Mean (SD) 7.382 (9.0602) 6.669 (7.3481) Median 7.130 5.950 Min, Max -17.60, 27.10 -10.46, 19.97 Vitality (Domain)Baseline n 41 43Mean (SD) 28.541 (5.3886) 29.083 (5.8541) Median 25.860 28.83073 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 1 Parameter 30 mg 1.5 mg Visit Statistic (N=41) (N=43)Min, Max 22.89, 43.69 22.89, 49.63 Day 28 change from Baseline n 38 36Mean (SD) 21.422 (14.3584) 16.452 (13.0568) Median 20.800 17.830 Min, Max -8.91, 44.56 -8.91, 44.56 Social Functioning (Domain)Baseline n 41 43Mean (SD) 29.584 (9.4518) 30.408 (9.6023) Median 27.260 32.270 Min, Max 17.23, 57.34 17.23, 52.33 Day 28 change from Baseline n 38 36Mean (SD) 20.052 (13.3913) 16.851 (13.1916) Median 20.050 17.545 Min, Max -15.04, 40.11 -10.03, 40.11 Role Limitations Due to Emotional Problems(Domain)Baseline n 41 43Mean (SD) 28.909 (11.3333) 26.938 (7.3723) Median 24.830 24.830 Min, Max 14.39, 56.17 14.39, 38.76 Day 28 change from Baseline n 38 36Mean (SD) 19.425 (14.3142) 17.990 (10.5455) Median 20.890 17.410 Min, Max -13.93, 41.78 -3.48, 34.82 Mental Health (Domain)Baseline n 41 43Mean (SD) 26.750 (6.3417) 27.203 (6.2523) Median 27.320 24.710 Min, Max 11.63, 37.79 16.86, 43.02 Day 28 change from Baseline n 38 36Mean (SD) 24.164 (13.5385) 19.402 (13.5494) Median 26.160 20.930 Min, Max -2.62, 47.09 -2.62, 39.24 Abbreviations: N = total number of participants per treatment group: n = number of participants reporting; SD = standard deviation.74 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)6.1.9.3.7 Assessment of Treatment Assignment by Participants and Efficacy Raters

[0235] In the 30 mg group, 13 (36.1%) participants responded they were “positive” and15 (41.7%) participants in the 30 mg group responded they “thought” they received the higher dose, whereas 7 (19.4%) participants in the 30 mg group responded they “couldn’t tell” their treatment assignment. The Bang’s Blinding Index (BBI) estimate of 0.556 supports the finding that the 30 mg group was moderately able to guess their treatment group.

[0236] Similar findings were reported for the raters: 7 (18.4%) raters were “positive” and 18 (47.4%) raters “thought”, whereas 10 (26.3%) raters “couldn’t tell” that the participants in the 30 mg group received the higher dose.

[0237] In the 1.5 mg group, 7 (18.4%) participants responded they were “positive” and 15 (39.5%) participants responded they “thought” they received the lower dose, whereas 11 (28.9%) responded they “couldn’t tell” their treatment assignment. The BBI estimate of 0.289 indicated that for the 1.5 mg group, it was more difficult to guess which treatment was received. Of the raters, 4 (10.8%) were “positive” and 7 (18.9%) “thought”, whereas 10 (27.0%) “couldn’t tell” that the participants in the 1.5 mg group received the lower dose. The BBI estimate of -0.041 suggests raters incorrectly guessed more often than random chance would predict in the 1.5 mg group (Table 22).Table 22. Blinding Efficacy Assessment (Full Analysis Set)Compound 1 Compound 1 Parameter 30 mg 1.5 mg Response Statistic (N=41) (N=43) Which treatment do you believe you received? N* 36 38 I am positive I received the higher dose of study drug n (%)a13 (36.1) 2 (5.3) I think I received the higher dose of study drug n (%) 15 (41.7) 3 (7.9) I cannot tell whether I received the higher dose of study drug n (%) 7 (19.4) 11 (28.9) I think I received the lower dose of study drag n (%) 1 (2.8) 15 (39.5) I am positive I received the lower dose of study drag n (%) 0 7 (18.4) Bang’s Blinding Index (Participant) Estimate 0.556 0.289 Which treatment do you believe the study participant received? N* 38 37 I am positive the study participant received the higher dose of study n(%) 7 (18.4) 2 (5.4) drugI think the study participant received the higher dose of study drag n(%) 18 (47.4) 14 (37.8)75 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)Compound 1 Compound 1 Parameter 30 mg 1.5 mg Response Statistic (N=41) (N=43) I cannot tell whether the study participant received the higher dose n (%) 10 (26.3) 10 (27.0) of study drugI think the study participant received the lower dose of study dmg n (%) 2 (5.3) 7 (18.9) I am positive the study participant received the lower dose of study n (%) 1 (2.6) 4 (10.8) dmgBang’s Blinding Index (Rater) Estimate 0.368 -0.041 N = total number of participants per treatment group; N* = number of participants who provided a response to the question; n = number of participants reporting.a. Percentages are based on tire number of participants in the Full Analysis Set with available data by treatment group.6.1.9.4 Statistical Issues Encountered During the Analysis

[0238] In general, subgroup results were comparable with the results of the primary analysis, showing a larger decrease (i.e., improvement in depression severity items) in the 30 mg group versus the 1.5 mg group. Of note, interpretation of some subgroup analyses were limited due to small sample size. The following notable differences within subgroups were observed and are shown in FIGs. 5A-5B:• Any prior episodes of PPD: ‘Yes’, ‘No’o Participants who reported prior episodes of PPD in the 30 mg group had greater decreases from Baseline in MADRS total score at Day 7 versus participants who did not report prior episodes of PPD (a mean [SD] change from Baseline of -28.4 [12.58] vs -21.5 [12.40]). This pattern was not seen with the 1.5 mg treatment group.• Prior hallucinogenic agent experience: ‘Yes’, ‘No’o Participants who reported prior experience with hallucinogenic agents in the 1.5 mg group had significantly smaller decreases from Baseline in MADRS total score at Day 7 versus participants who did not report prior experience with hallucinogenic agents (a mean [SD] change from Baseline of 0.7 (10.79) vs -18.9 (10.99)). This pattern was not seen with the 30 mg treatment group.• Baseline MADRS total score: <30, >30o Participants with Baseline MADRS total scores <30 had smaller decreases from Baseline in both dose groups than participants with Baseline MADRS total scores >30. A larger difference was seen for 30 mg (a mean [SD] change from Baseline of -11.5 [10.94] vs -28.0 [10.02]). This differential impact resulted in a treatment effect of 9.5 in the MADRS total scores > 30 subgroup.76 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)• Concomitant psychotherapy: Yes, Noo Participants who reported concomitant psychotherapy were more common in the 30 mg group (8 participants vs 2) and had smaller decreases from Baseline in both dose groups than participants who did not have concomitant psychotherapy. A larger difference was seen for 30 mg (a mean [SD] change from Baseline of -16.4 [11.25] vs -25.0 [12.56]). This differential impact resulted in a treatment effect of 7.5 in the no concomitant psychotherapy group.• MADRS version: ‘Correct Lookback’, ‘Incorrect Lookback’o The number of participants with an ‘Incorrect Lookback’ was balanced between treatment groups. Within the ‘Incorrect Lookback’ subgroup, a smaller decrease from Baseline was observed in the 30 mg group compared with the 1.5 mg group (mean [SD] change of -17.8 [18.99] vs -21.7 [16.14]). These findings suggest that the use of an incorrect version of the MADRS may have contributed to a potential blunting of the treatment effect.6.1.9.5 Efficacy Results Summary

[0239] The primary efficacy endpoint was met. Compound 130 mg showed a statistically significant greater reduction from Baseline in MADRS total score at Day 7 compared to that of compound 1 1.5 mg (control), supporting the alternative hypothesis (i.e., the decrease from Baseline in the 30 mg group was larger than that in the 1.5 mg group), with an LSM difference (SE) of -5.80 points (2.466) (90% CI: -9.85, -1.74; one-sided P = 0.0094).

[0240] Both groups showed improvement after Baseline on the MADRS at other timepoints with a consistent LSM (SE) change from Baseline in the 30 mg group of -23.45 (1.632), -24.12 (1.719) and -23.81 (1.847) at Day 1, 14 and 28, respectively. Three quarters of participants began the study with severe depressive symptoms (mean MADRS total scores at Baseline were >30 in both groups). The improvement in MADRS scores at Day 7 was such that 77.14% of participants in the 30 mg group and 61.54% participants in the 1.5 mg group were considered treatment responders (i.e., had a >50% reduction in MADRS total score from Baseline), and 30.4% more participants in the 30 mg group compared to the 1.5 mg group were considered remitters (71.43% of participants in the 30 mg group and 41.03% participants in the 1.5 mg group).

[0241] Similarly, both groups showed improvement on the CGI-I, but improvement was greater in the 30 mg group at Days 1 and 7, whereas the scores were comparable at Day 28. On Day 1,77 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)63.4% in the 30 mg group and 50.0% in the 1.5 mg group were CGI-I responders. By Day 7, these rates increased to 76.3% and 60.0%, respectively. At Day 28, 71.8% in the 30 mg group and 73.0% in the 1.5 mg group were responders.

[0242] At the start of the study, all participants were considered at least moderately ill on the CGI-S. At Day 1, the majority of participants in both groups shifted toward less severe illness, with 14.6% of the 30 mg group and 7.1% of the 1.5 mg group rated as ‘Normal, not ill at all’ and fewer participants taking 30 mg remained ‘Moderately ill’ (17.1%) compared to the 1.5 mg group (42.9%). At Day 7, 18.4% of the 30 mg group and 12.5% of the 1.5 mg group were ‘Normal’. At Day 28, 41.0% of the 30 mg group and 27.0% of the 1.5 mg group were ‘Normal’, with other severity levels being similar between groups.

[0243] HAM-A scores were relatively low at Baseline and both groups also demonstrated improvement in anxiety symptoms as measured by the reduction in HAM-A total score; at Day 7 (LSM [SE] changes were -10.59 [1.154] for the 30 mg group and -9.58 [1.117] for the 1.5 mg group.

[0244] As expected, participants in the 30 mg group had a stronger mystical experience, as measured by higher scores on the MEQ-4 (mean [SD] / median MEQ-4 total scores for the 30 mg and the 1.5 mg group were 3.213 [1.3493] / 3.500 and 1.733 [1.2433] / 1.500, respectively).Similarly, participants in the 30 mg group also reported a more intense challenging experience as measured by the CEQ-7 (mean [SD] / median CEQ-7 total scores of 19.30 [18.798] / 14.29 and 9.10 [13.959] / 2.86 for the 30 mg and the 1.5 mg group, respectively).

[0245] Changes in other measures of depression severity were consistent with MADRS results. From Baseline to Day 7, both the 30 mg and 1.5 mg groups showed improvements in EPDS scores, with the 30 mg group experiencing a greater reduction. Changes in mean (SD) / median EPDS total scores from Baseline to Day 7 for the 30 mg and the 1.5 mg group were -12.6 (7.50) / -14.0 or a shift from severe to no depression and -10.8 (7.04) / - 11.5 or a shift from severe to possible mild depression, respectively.

[0246] Similarly, from Baseline to Day 14, PHQ-9 scores also improved in both groups, with the 30 mg group showing a slightly larger decrease. Changes in mean (SD) / median PHQ-9 total scores from Baseline to Day 14 for the 30 mg and the 1.5 mg group were -14.1 (6.27) / -14.5 or a78 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)shift from moderately severe to none to minimal depression and -12.9 (6.61) / -14.0 or a shift from moderately severe to mild depression, respectively.

[0247] At Baseline, participants in both the 30 mg and 1.5 mg groups had similar levels of maternal functioning impairment as measured by the BIMF. Maternal functioning improved in both groups at Day 7, with a higher change in mean (SD) BIMF total scores from Baseline in the 30 mg group (30.7 [19.57]) than the 1.5 mg group (18.6 [14.71]).

[0248] At Day 28, SF-36 results demonstrated improvements in the ‘mental health (summary component)’ in both treatment groups, with a mean (SD) score of 47.275 (13.4594) in the 30 mg group and 42.964 (15.7107), in the 1.5 mg group. The greatest increase was observed in the 30 mg group, as indicated by the mean (SD) change from Baseline of 28.837 (16.6880) and 23.421 (15.7605) for the 30 mg and the 1.5 mg group, respectively. Higher scores indicate better health and functioning.

[0249] Results of the blinding assessment suggest that the 30 mg group was moderately able to guess their treatment group, as a considerable percentage of participants correctly guessed their treatment assignment (36.1% were “positive” and 41.7% “thought” they received the higher dose). Similarly, raters often guessed the correct treatment assignment (18.4% were “positive” and 47.4% “thought” the participants received the higher dose). In contrast, blinding was more effective in the 1.5 mg group. Only 18.4% of participants were “positive” and 39.5% “thought” they received the lower dose, while 28.9% “couldn’t tell”. Raters in the 1.5 mg group were effectively blinded, with a BBI of -0.041, suggesting they guessed incorrectly more often than chance.6.1.10. Safety Results Summary

[0250] No SAEs, treatment-emergent deaths, or TEAEs leading to withdrawal were reported in the study.

[0251] Overall, TEAEs were reported in 77.4% participants with a notably higher percentage reported in the 30 mg group (92.7%) compared to the 1.5 mg group (62.8%). The observed difference in overall AE reporting rates between the 30 mg and 1.5 mg groups may be attributable to the anticipated variability in psychedelic experience, which constitutes an inherent component of the treatment effect. In the 30 mg group, the most frequent TEAEs were nausea79 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)(43.9%), headache (34.1%), and dizziness (26.8%). In the 1.5 mg group, headache (18.6%) and nausea (16.3%) were most frequent, while dizziness, tremor, anxiety, and injection site pain were each reported in 7.0% of participants. These TEAEs largely occurred during the dosing period and were expected based on the pharmacological profile of the study drug.

[0252] Overall, most TEAEs were mild (53.6% participants) or moderate (21.4% participants) with a similar distribution of TEAE severity between groups. Severe TEAEs were reported in 2 (4.9%) participants, both in the 30 mg group: 1 (2.4%) participant had nausea (related to compound 1) and 1 (2.4%) participant had cannabinoid hyperemesis syndrome (unrelated to compound 1).

[0253] AESIs defined for this study included Psychiatric AESIs (indicative of abuse potential) and potential seizure-related AESIs. Over half of participants overall (54.8%) had AESIs, with a greater proportion occurring the 30 mg versus the 1.5 mg group (75.6% versus 34.9%, respectively). All AESIs belonged to the Psychiatric AESIs category, the most frequent of which were visual hallucination, anxiety, and illusion. Most of these TEAEs occurred during the dosing period, were mild or moderate in severity and resolved either spontaneously or with non-pharmacological techniques provided by Session Monitors (e.g., grounding practices).

[0254] Most laboratory parameters remained stable during the study. For hematology, shifts occurred among >5% of participants in erythrocyte count, mean corpuscular hemoglobin concentration, mean corpuscular volume, hematocrit, hemoglobin, and leukocytes. For chemistry shifts in >5% of participants included alterations in alanine aminotransferase, aspartate aminotransferase, bilirubin, glucose, protein, and urea nitrogen levels. Urinalysis shifts were reported for specific gravity, ketones, leukocyte esterase, occult blood, and protein. There were no TEAEs related to clinically significant abnormalities in hematology, chemistry, or urinalysis parameters during the study.

[0255] Most vital sign parameters remained stable during the study, except for small variations in blood pressure on Day 0 up to 5 hours after dosing and a slight increase in pulse rate through Day 28. One mild TEAE related to vital signs was reported in the 1.5 mg group (subjective increased heart rate in 1 participant). Overall, 2 mild TEAE associated with palpitations were reported (2 [2.4%] participants), 1 in each treatment group. Only the event occurring in the 30 mg group was considered treatment related TEAE.80 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)

[0256] No relevant physical examination findings were reported during the study.

[0257] All participants had negative pregnancy results at Screening and Day 0. Pregnancy was reported in 1 participant on Day 28 in the 30 mg group. The participant delivered a healthy, female infant via cesarean section on 03 Aug 2025. There were no complications, and the participant and baby were discharged from hospital on 06 Aug 2025.

[0258] Overall, QTcF parameter results showed that the majority of participants in both dose groups remained within normal limits throughout the study. Most participants had no shift in ECG interpretation from Baseline and most ECGs were interpreted as normal or abnormal but not clinically significant at both Baseline and post-baseline assessments. ECG-related TEAEs included sinus tachycardia (1 participant in the 30 mg group) and tachycardia (1 participant in the 30 mg group). All the events were of mild severity and resolved on the same day.

[0259] At Baseline, over half of participants reported a lifetime history of suicidal ideation — 56.1% in the 30 mg group and 48.8% in the 1.5 mg group. A lifetime history of suicidal behavior was also reported at Baseline by 19.5% of participants in the 30 mg group and 27.9% in the 1.5 mg group. No participants reported suicidal behavior after Baseline, and no treatment-emergent ideation or behavior was observed during the study. There was 1 TEAE of suicidal ideation in the 1.5 mg treatment group. However, the participant had active suicidal ideation prior to dosing and was using oral bupropion (once daily; throughout the study) for the treatment of suicidal ideation with method. The event occurred 22 days after dosing, was mild, resolved after 2 weeks without any additional pharmacological treatment, and was considered as unrelated to compound 1 by the Investigator.

[0260] Based on BPRS+ results, no worsening of positive symptoms of psychosis was observed over the study. There were no TEAEs of psychosis or worsening of PPD symptoms defined as the presence of a significant risk of suicide as assessed by C-SSRS and / or MADRS, worsening in symptoms as assessed by CGI-I, or in the study physician’s judgment throughout the study.

[0261] By 6 hours post-dose, no participants in either group reported or exhibited signs of confusion, anxiety, paranoia, delusions, suicidality, or psychotic symptoms nor did any participant display symptoms or signs that posed a risk for discharge. At 7 hours post-treatment, 41 / 41 (100%) participants in the 30 mg group and 37 / 39 (94.9%) in the 1.5 mg group indicated81 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)that they felt safe and competent to leave. By 8-hours post-dose, all participants had blood pressure and heart rate acceptable for release and were ready to be discharged.7. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0262] 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.

[0263] 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.82 of 924913-6380-0984

Claims

1. Attorney Ref: 145737-0191 (007WO2)WHAT IS CLAIMED IS:

1. A method of treating a psychological disease or disorder in a subject in need thereof, the method comprising conjointly administering to the subject a therapeutically effective amount of compound 1, wherein compound 1 is represented by:NHor is a zwitterion or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant).

2. The method according to claim 1, wherein the psychological disease or disorder is selected from: generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

3. The method according to claim 1 or 2, wherein the psychological disease or disorder is selected from: depression, major depressive disorder (MDD), postpartum depression (PPD), and drug-resistant depression.

4. The method according to claim 3, wherein the psychological disease or disorder is PPD.

5. The method according to claim 4, wherein the subject is no more than 15 months postpartum.

6. The method according to any one of claims 3-5, wherein the subject is diagnosed with PPD prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.83 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)7. The method according to claim 6, wherein the subject is diagnosed with PPD according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders Clinical Trial Version (SCID-5-CT).

8. The method according to any one of claims 1-7, wherein the subject has a Montgomery - Asberg Depression Rating Scale (MADRS) score of at least 20 when the subject is evaluated prior to administration of compound 1, such as on Day 0 prior to administration of compound 1.

9. The method according to any one of claims 6-8, wherein the subject has a Hamilton Rating Scale for Depression (HAMD-17) score of at least 24 when the subject is evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

10. The method according to any one of claims 6-9, wherein the subject has a Clinical Global Impression-Severity (CGI-S) score of at least 3 when evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

11. The method according to any one of claims 4-10, wherein the subject has been on a stable regimen of a SSRI for at least 30 days prior to administration of compound 1.

12. The method according to any one of claims 4-10, wherein the subject has been on established psychotherapy for at least 30 days prior to administration of compound 1.

13. The method according to any one of the preceding claims, wherein compound 1 and the second therapeutic agent are administered concomitantly.

14. The method according to any one of the preceding claims, wherein compound 1 and the second therapeutic agent are administered sequentially.

15. The method according to any one of the preceding claims, wherein compound 1 is administered by injection, such as subcutaneous injection.

16. The method according to any one of the preceding claims, wherein compound 1 is administered to the subject in a medical facility.

17. The method according to claim 16, wherein the subject remains in the medical facility for at least 8 hours following administration of compound 1.84 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)18. The method according to any one of the preceding claims, wherein compound 1 is administered to the subject by a medically trained professional.

19. The method according to any one of the preceding claims, wherein compound 1 is administered in an amount from 1 mg to 60 mg (calculated as the free base or HC1 salt), such as 1.5 mg (free base) or 1.65 mg (HC1 salt).

20. The method according to any one of the preceding claims, wherein compound 1 is administered in an amount from 20 mg to 60 mg (calculated as the free base or HC1 salt), such as 30 mg (free base) or 33 mg (HC1 salt).

21. The method according to any one of the preceding claims, wherein compound 1 is administered as a single dose.

22. The method according to claim 21, wherein the single dose is in the form of a solution.

23. The method according to any one of the preceding claims, wherein compound 1 is administered to the patient as the zwitterion of compound 1.

24. The method according to any one of the preceding claims, wherein the second therapeutic agent is a SSRI.

25. The method according to claim 24, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

26. The method according to any one of claims 4-25, wherein the subject exhibits reduced depressive symptoms following administration of compound 1 compared to the subject’s depressive symptoms prior to administration of compound 1 (baseline).

27. The method according to any one of claims 4-26, wherein the subject’s MADRS score following administration of compound 1 is reduced by at least 50% compared to the subject’s MADRS score prior to administration of compound 1 (baseline).

28. The method according to any one of claims 4-27, wherein the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and wherein the subject’s MADRS score following administration of compound 1 is evaluated 1, 7, 14 or 28 days after administration of compound 1 (i.e., Day 1, Day 7, Day 14, and Day 28).85 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)29. The method according to claim 28, wherein the subject’s MADRS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.

30. The method according to any one of claims 4-29, wherein the subject’s MADRS score is 10 or less following administration of compound 1.

31. The method according to claim 30, wherein the subject’s MADRS score is 10 or less 7 days after administration of compound 1 (Day 7).

32. The method according to any one of claims 4-31, wherein the subject’s Clinical Global Impression-Improvement (CGI-I) score demonstrates improvement in depressive symptoms following administration of compound 1.

33. The method according to any one of claims 4-32, wherein the subject’s CGI-I score is 3 or less, such as 3, 2 or 1 following administration of compound 1.

34. The method according to any one of claims 4-33, wherein the subject’s CGI-I score is evaluated 1, 7, or 28 days following administration of compound 1 (i.e., Day 1, Day 7, and Day 28).

35. The method according to any one of claims 4-34, wherein the subject’s CGI-severity score (CGI-S) score is improved following administration of compound 1 compared to the subject’s CGI-S score prior to administration of compound 1 (baseline).

36. The method according to any one of claims 4-35, wherein the subject’s CGI-S score decreases by at least 1 following administration of compound 1 compared to the subject’s baseline CGI-S score.

37. The method according to any one of claims 4-36, wherein the subject’s CGI-S baseline score is evaluated one day prior to administration of compound 1 (Day -1); and wherein the subject’s CGI-S score following administration of compound 1 is evaluated 1, 7, or 28 days after administration of compound 1 (i.e., Day 1, Day 7, and Day 28).

38. The method according to any one of claims 4-37, wherein the subject exhibits reduced anxiety symptoms following administration of compound 1 compared to the subject’s anxiety symptoms prior to administration of compound 1 (baseline).86 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)39. The method according to any one of claims 4-38, wherein the subject’s Hamilton Rating Scale for Anxiety (HAM-A) score is improved following administration of compound 1 compared to the subject’s HAM-A score prior to administration of compound 1 (baseline).

40. The method according to any one of claims 4-39, wherein the subject’s HAM-A score is less than 30, preferably less than 25.

41. The method according to any one of claims 4-40, wherein the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and wherein the subj ect’ s HAM-A score following administration of compound 1 is evaluated 1, 7, 14 or 28 days after administration of compound 1 (i.e., Day 1, Day 7, Day 14, and Day 28).

42. A method of treating a psychological disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of compound 1, wherein the subject (a) has been on a stable regimen of at least one SSRI for at least 30 days prior to administration of compound 1 or (b) has been on established psychotherapy for at least 30 days prior to administration of compound 1.

43. The method of claim 42, wherein the psychological disease or disorder is selected from:GAD, MDD, PPD, drug-resistant depression, alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, OCD, and PTSD.

44. The method according to claim 42 or 43, wherein the psychological disease or disorder is selected from depression, MDD, PPD, and drug-resistant depression.

45. The method according to claim 44, wherein the psychological disease or disorder is PPD.

46. The method according to claim 45, wherein the subject is no more than 15 months postpartum.

47. The method according to claim 45 or claim 46, wherein the subject is diagnosed with PPD prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.87 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)48. The method according to any one of claims 45-47, wherein the subject is diagnosed with PPD according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders Clinical Trial Version (SCID-5-CT).

49. The method according to any one of claims 45-48, wherein the subject has a MADRS score of at least 20 when the subject was evaluated prior to administration of compound 1, such as on Day 0 prior to administration of compound 1.

50. The method according to any one of claims 45-49, wherein the subject has a Hamilton Rating Scale for Depression (HAMD-17) score of at least 24 when the subject is evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

51. The method according to any one of claims 45-50, wherein the subject has a Clinical Global Impression-Severity (CGI-S) score of at least 3 when evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

52. The method according to any one of claims 42-51, wherein the subject has been on a stable regimen of a SSRI for at least 30 days prior to administration of compound 1.

53. The method according to claim 52, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

54. The method according to any one of claims 42-51, wherein the subject has been on established psychotherapy for at least 30 days prior to administration of compound 1.

55. The method according to claim 54, wherein the psychotherapy is selected from cognitive behavioral therapy (CBT) (e.g., dialectical behavior therapy (DBT), rational emotive behavior therapy (REBT), acceptance and commitment therapy (ACT)), behavioral therapy (e.g., systematic desensitization, aversion therapy, flooding), psychodynamic therapy, humanistic therapy (e.g., gestalt therapy, person-centered therapy, existential therapy), interpersonal therapy, and supporting therapy.

56. The method according to any one of claims 42-55, wherein compound 1 is administered by injection, such as subcutaneous injection.88 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)57. The method according to any one of claims 42-56, wherein compound 1 is administered to the subject in a medical facility.

58. The method according to claim 57, wherein the subject remains in the medical facility for at least 8 hours following administration of compound 1.

59. The method according to any one of claims 42-58, wherein compound 1 is administered to the subject by a medically trained professional.

60. The method according to any one of claims 42-59, wherein compound 1 is administered in an amount from 1 to 60 mg (calculated as the free base or HC1 salt), such as 1.5 mg (free base) or 1.65 mg (HCl salt).

61. The method according to any one of the preceding claims, wherein compound 1 is administered in an amount from 20 mg to 60 mg (calculated as the free base or HC1 salt), such as 30 mg (free base) or 33 mg (HC1 salt).

62. The method according to any one of claims 42-61, wherein compound 1 is administered as a single dose.

63. The method according to claim 62, wherein the single dose is in the form of a solution.

64. The method according to any one of claims 42-63, wherein compound 1 is administered to the patient as the zwitterion of compound 1.

65. The method according to any one of claims 45-64, wherein the subject exhibits reduced depressive symptoms following administration of compound 1 compared to the subject’s depressive symptoms prior to administration of compound 1 (baseline).

66. The method according to any one of claims 45-65, wherein the subject’s MADRS score following administration of compound 1 is reduced by at least 50% compared to the subject’s MADRS score prior to administration of compound 1 (baseline).

67. The method according to any one of claims 45-66, wherein the subject’s MADRS baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and wherein the subject’s MADRS score following administration of compound 1 is evaluated 1, 7, 14 or 28 days after administration of compound 1 (i.e., Day 1, Day 7, Day 14, and Day 28).89 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)68. The method according to claim 67, wherein the subject’s MADRS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.

69. The method according to any one of claims 45-68, wherein the subject’s MADRS score is 10 or less following administration of compound 1.

70. The method according to claim 69, wherein the subject’s MADRS score is 10 or less 7 days after administration of compound 1 (Day 7).

71. The method according to any one of claims 45-70, wherein the subject’s Clinical Global Impression-Improvement (CGI-I) score demonstrates improvement in depressive symptoms following administration of compound 1.

72. The method according to any one of claims 45-71, wherein the subject’s CGI-I score is 3 or less, such as 3, 2 or 1 following administration of compound 1.

73. The method according to any one of claims 45-72, wherein the subject’s CGI-I score is evaluated 1, 7, or 28 days following administration of compound 1 (i.e., Day 1, Day 7, and Day 28).

74. The method according to any one of claims 45-73, wherein the subject’s CGI-severity score (CGI-S) score is improved following administration of compound 1 compared to the subject’s CGI-S score prior to administration of compound 1 (baseline).

75. The method according to any one of claims 45-74, wherein the subject’s CGI-S score decreases by at least 2 following administration of compound 1 compared to the subject’s baseline CGI-S score.

76. The method according to any one of claims 45-75, wherein the subject’s CGI-S baseline score is evaluated one day prior to administration of compound 1 (Day -1); and wherein the subject’s CGI-S score following administration of compound 1 is evaluated 1, 7, or 28 days after administration of compound 1 (i.e., Day 1, Day 7, and Day 28).

77. The method according to any one of claims 45-76, wherein the subject exhibits reduced anxiety symptoms following administration of compound 1 compared to the subject’s anxiety symptoms prior to administration of compound 1 (baseline).90 of 924913-6380-0984Attorney Ref: 145737-0191 (007WO2)78. The method according to any one of claims 45-77, wherein the subject’s HAM-A score is improved following administration of compound 1 compared to the subject’s HAM-A score prior to administration of compound 1 (baseline).

79. The method according to any one of claims 45-78, wherein the subject’s HAM-A score is less than 30, preferably less than 25.

80. The method according to any one of claims 45-79, wherein the subject’s HAM-A baseline score is evaluated on the same day, but prior to, administration of compound 1 (Day 0); and wherein the subject’s HAM-A score following administration of compound 1 is evaluated 1, 7, 14 or 28 days after administration of compound 1 (i.e., Day 1, Day 7, Day 14, and Day 28).

81. Use of a therapeutically effective amount of compound 1 and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant) for manufacturing a medicament for treating a psychological disease or disorder (e.g., PPD).

82. Use of a therapeutically effective amount of compound 1 and a therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant) for treating a psychological disease or disorder (e.g., PPD).91 of 924913-6380-0984

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