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 (compound 1) 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 psychotherapy by administration of compound 1 or a pharmaceutically acceptable salt or zwitterion thereof.

Description

Atorney Ref: 42790-62103 (007WO1)METHODS OF USING TRYPTAMINE PRODRUGS1. BACKGROUND

[0001] 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)

[0002] Additional symptoms associated with PPD include irritability, mood lability, anxiety, thoughts of harming the child, and obsessional worries or preoccupations with baby.

[0003] The worldwide incidence and prevalence of PPD is approximately 12% and 17%, respectively. Risk factors for PPD include history of depression and anxiety, complicated pregnancy including emergency cesarean section, lack of social support, and lifestyle choices (eating habits, sleep cycle, physical activities, and exercise).

[0004] 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,Attorney Ref: 42790-62103 (007WO1)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.

[0005] In patients with moderate or severe PPD, 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 is indicated for the treatment of moderate to severe PPD. A similar compound, zuranalone, is currently under review by the Agency for the treatment of major depressive disorder and PPD. Brexanolone is administered as a single dose intravenous (IV) infusion requiring several dose titration steps over a continuous infusion period of 60 hours and has a boxed warning for excessive sedation and sudden loss of consciousness, requiring continuous monitoring. While brexanolone provides a rapid response with a decrease in depressive symptoms in patients with moderate to serious PPD documented 24 hours postinfusion, it is only available through a restricted program under the Zulresso Risk Evaluation and Mitigation Strategy program. Along with the high cost of treatment, these restrictions present a significant barrier to its access and wide-spread use.

[0006] 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 Psilcybe mushrooms or the drug substance is taken orally:Psilocybin PsilocinAtorney Ref: 42790-62103 (007WO1)

[0007] Compound 1 (4-Glutaroyl-3-[2-diisopropylaminoethyl]-lH-indole hydrochloride) is a prodrug of the synthetic psychedelic drug 3-(2-diisopropylaminoethyl)-lH-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.

[0008] 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, 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:Compound 1 HC1 4-OH-DiPT Psilocin (4-OH-DMT)

[0009] 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).

[0010] 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.Atorney Ref: 42790-62103 (007WO1)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).

[0011] 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 that the overall safety profile of RE 104 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 (approx Ih), 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.

[0012] 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.2. SUMMARY

[0013] 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:Atorney Ref: 42790-62103 (007W01)or is a zwitterion or a pharmaceutically acceptable salt thereof, anda therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant).

[0014] 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 compound 1 is represented by:or is a zwitterion or a pharmaceutically acceptable salt thereof, wherein the subject (a) has been on a stable regimen of SSRIs for at least 30 days prior to administration of compound 1 or (b) has been on a stable psychotherapy regimen for at least 30 days prior to administration of compound 1.

[0015] 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 stable psychotherapy regimen. 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.

[0016] 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.Attorney Ref: 42790-62103 (007WO1)

[0017] 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.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] 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:

[0019] FIG. 1 shows a scheme of the clinical trial described in Example 1.

[0020] FIGs.2A-2B show the Schedule of Activities (SoA) for the clinical trial described in Example 1. With respect to the SoA:aVI 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.8Urine 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).1Vital 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.Attorney Ref: 42790-62103 (007WO1)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.1The 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. *Note that for the Day 1 assessment only, the 24-hour recall version of the MADRS (MADRS-24hr) will be 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 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.1Remote 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.4. DETAILED DESCRIPTION4.1. Definitions

[0021] 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.

[0022] 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 asAtorney Ref: 42790-62103 (007WO1)“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 least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B .”Atorney Ref: 42790-62103 (007WO1)

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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 aAttorney Ref: 42790-62103 (007WO1)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.

[0027] As used herein, the term “established psychotherapy” refers to therapy that has been stable in terms of frequency for a given timeframe (e.g., at least 30 days).

[0028] 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 acid 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-phenylpropionate, 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.Atorney Ref: 42790-62103 (007WO1)

[0029] 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.

[0030] As used herein, a “stable regimen” refers to a subject’s maintenance dosing regimen for a particular drug (e.g., SSRIs) 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.

[0031] 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. 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.

[0032] 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.

[0033] 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, theAttorney Ref: 42790-62103 (007W01)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.4.2. Methods

[0034] 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 comprising co-jointly 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, anda therapeutically effective amount of a second therapeutic agent (e.g., an antidepressant).

[0035] Conjoint administration contemplates that the second therapeutic agent can be administered concomitantly, prior to, or after administration of compound 1.

[0036] 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.

[0037] 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 hourAtorney Ref: 42790-62103 (007W01)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.

[0038] 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.

[0039] In certain embodiments, the second therapeutic agent is an antidepressant. In certain embodiments, the antidepressant is a selective serotonin reuptake inhibitor (SSRI).

[0040] In certain embodiments, the antidepressant is a serotonin modulator, such as vilazodone, trazodone, nefazodone, or vortioxetine.

[0041] In certain embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor (SNRI), e.g., venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, sibutramine, or tramadol.

[0042] 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.

[0043] 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.

[0044] In certain embodiments, the antidepressant is a tricyclic, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, loxapine, nortriptyline, olanzapine, protriptyline, quetiapine, and trimipramine.

[0045] In certain embodiments, the antidepressant is selected from aptazapine, esmirtazapine, benzoctamine, maprotiline, mianserin, mirtazapine, oxaprotiline, and setiptiline.

[0046] In certain embodiments, the antidepressant is a neurosteroid, such as allopregnanolone, brexanolone, ganaxolone, or zuranolone.Attorney Ref: 42790-62103 (007WO1)

[0047] In certain embodiments, the antidepressant is an MAO inhibitor, such as phenelzine, isocarboxazid, selegiline, or tranylcypromine.

[0048] In certain embodiments, the second therapeutic agent is a SSRI. Exemplary SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

[0049] 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 compound 1 is represented by:or is a zwitterion or a pharmaceutically acceptable salt thereof, wherein the subject (a) has been on a stable regimen of SSRIs for at least 30 days prior to administration of compound 1 or (b) has been on a stable psychotherapy regimen for at least 30 days prior to administration of compound 1.

[0050] 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).

[0051] 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.

[0052] 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.Attorney Ref: 42790-62103 (007WO1)

[0053] 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.

[0054] In certain embodiments, the subject is not breastfeeding.

[0055] 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).

[0056] In certain embodiments, the subject was diagnosed with PPD prior to administration of compound 1 (administration of compound 1 = Day 0). In certain embodiments, the subject was diagnosed with PPD in the 21 days prior to administration of compound 1 (Day -1 to Day -21). In certain embodiments, the subject was diagnosed with PPD according to the SCID-5-CT prior to administration of compound 1. In certain embodiments, the subject was diagnosed with PPD according to SCID-5-CT in the 21 days prior to administration of compound 1 (Day -1 to Day -21).

[0057] In certain embodiments, the subject experienced symptoms of depression prior to administration of compound 1. In certain embodiments, the subject experienced symptoms of depression in the 21 days prior to administration of compound 1 (Day -1 to Day -21). In certain embodiments, the subject experienced symptoms of depression according to the Hamilton Rating Scale for Depression (HAMD-17), when the subject’s HAMD-17 score was evaluated in the 21 days prior to administration of compound 1 (Day -1 to Day -21). In certain embodiments, the subject had a HAMD-17 score of 24 or higher when the subject was evaluated in the 21 days prior to administration of compound 1 (Day -1 to Day -21).Attorney Ref: 42790-62103 (007WO1)

[0058] 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).

[0059] In certain embodiments, the subject was diagnosed with PPD and experienced symptoms of depression prior to administration of compound 1.

[0060] In certain embodiments, the subject was diagnosed with PPD according to SCID-5-CT and experienced 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 was diagnosed with PPD according to SCID-5-CT, had a HAMD-17 score of 24 or higher, and / or had a CGI-S score of at least 3 prior to administration of compound 1. In certain embodiments, when the subject was evaluated in the 21 days prior to administration of compound 1 (Day -1 to Day -21), the subject was diagnosed with PPD according to SCID-5-CT, had a HAMD-17 score of 24 or higher, and / or had a CGI-S score of at least 3.

[0061] 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.

[0062] In certain embodiments, the subject has not used serotonin-norepinephrine reuptake inhibitors prior to prior to administration of compound 1, e.g., in the 14 days prior to administration of compound 1.

[0063] In certain embodiments, the subject has not used psychedelics such as 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 form prior to administration of compound 1, e.g., in the 12 months prior to administration of compound 1.

[0064] In certain embodiments, the subject has not used psychoactive medication or a medication with monoamine oxidase activity (such as isocarboxazid, phenelzine, selegiline orAtorney Ref: 42790-62103 (007W01)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.

[0065] In certain embodiments, the subject has not used synthetic or naturally occurring cannabinoids prior to administration of compound 1.

[0066] 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.

[0067] In certain embodiments, the subject has been on a stable regimen of a selective serotonin reuptake inhibitor (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.

[0068] Exemplary SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

[0069] In certain embodiments, the subject has been on a stable psychotherapy regimen 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.

[0070] 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.Attorney Ref: 42790-62103 (007WO1)

[0071] In certain embodiments, compound 1 is administered to the subject by a medically trained professional, e.g., a pharmacist, nurse, or doctor.

[0072] 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 azwitterion(1).

[0073] In certain embodiments, compound 1 is administered in the form of a solution suitable for injection, e.g., intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous injections. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle free injectors and infusion techniques.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] A typical injectable solution is produced by aseptically placing at least one of the compounds of the present invention (e.g., 33 mg) into a vial as a sterile filtered solution, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with, forAtorney Ref: 42790-62103 (007WO1)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.

[0078] In certain embodiments, from 20 mg to 60 mg of compound 1 (calculated as the free base or HC1 salt) is administered to the subject in a single dose, e.g., 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 HC1 salt) is administered to the subject in a single dose.

[0079] In certain embodiments, from 20 mg / mL to 60 mg / mL of compound 1 (calculated as the free base or HC1 salt) is administered to the subject in a single dose in the form of a solution, e.g., 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 HC1 salt) is administered to the subject in a single dose in the form of a solution.

[0080] 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.

[0081] In certain embodiments, the subject exhibits reduced depressive symptoms following administration of compound 1 compared to the subject’s depressive symptoms prior to treatment (baseline). In certain embodiments, the subject’s Montgomery-Asberg Depression Rating Scale (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 MARDS score following administration of compound 1 is evaluated 1Atorney Ref: 42790-62103 (007W01)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 MARDS 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 MARDS score following administration of compound 1 is evaluated 14 days after administration of compound 1 (Day 14). 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 MARDS score following administration of compound 1 is evaluated 28 days after administration of compound 1 (Day 28). In certain embodiments, the subject’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 MARDS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.

[0082] 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 MARDS score of 10 or less, 8 or less, 6 or less, 4 or less, 2 or less, or 0. In certain embodiments, the subject’s MADRS score is 10 or less 7 days after administration of compound 1 (Day 7).

[0083] 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).

[0084] 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 scoreAtorney Ref: 42790-62103 (007WO1)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.

[0085] 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).

[0086] 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).

[0087] 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).Attorney Ref: 42790-62103 (007WO1)

[0088] 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 or moderate depression following administration of compound 1. 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 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).

[0089] 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).

[0090] 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.

[0091] 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 scoreAtorney Ref: 42790-62103 (007WO1)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 score 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).

[0092] 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.

[0093] 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).

[0094] 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).Atorney Ref: 42790-62103 (007WO1)5. EXAMPLES5.1. 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)5.1.1. Summary

[0095] This is 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), the study drug, in the treatment of adult female patients with PPD. This study will be conducted at approximately 35 study centers in the United States.

[0096] A schema of the trial is provided in FIG. 1. A schedule of Activities (SoA) for the trial is provided in FIG.2.

[0097] Approximately 72 patients (36 per dose group) will be 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 will have 4 periods: a Screening Period of up to 21 days, a 2-day Baseline Period consisting of baseline assessments on Day -1 and up through predosing on Day 0, immediately followed by the Treatment Period, which begins with study drug administration and during which patients will be monitored in-clinic for 8 hours before being discharged on Day 0, and a 28-day Follow-Up Period.Objectives and Endpoints:

[0098] The objectives and endpoints of the study are provided in Table 1.Table 1. Endpoints and ObjectivesAtorney Ref: 42790-62103 (007W01)><Atorney Ref: 42790-62103 (007WO1)Screening Period:

[0099] The Screening Period begins when a patient provides written consent prior to any study-related assessments. Patients will be 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.

[0100] During the Screening Period, patients will be 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 will be assessed via Hamilton Depression Rating Scale (HAMD-17) using the Structured Interview Guide for the Hamilton Depression Rating Scale- 17 Item Version (SIGH-D-17), and Clinical Global Impression-Severity (CGI-S) score.Baseline Period:

[0101] Pre-dose assessments will be 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 will be randomized on the day of dosing (Day 0) to 1 of 2 dose levels of compound 1 (30 mg or 1.5 mg), stratified by Montgomery-Asberg Depression Rating Scale (MADRS) baseline total score into 2 groups (total score <30 and >30).Treatment Period:

[0102] The study drug will be prepared and administered as a subcutaneous (SC) injection.

[0103] The dosing session will be supported by 2 qualified Session Monitors and will be video recorded for training and adherence monitoring.

[0104] Patients will remain in the clinic under general observation for post-dose routine safety monitoring and discharge readiness per the Schedule of Activities (SoA) for 8 hours.

[0105] Once deemed ready for discharge patients will be allowed to go home and must be escorted by a trusted friend or family member, or caregiver.

[0106] The 8-hour post-dose discharge readiness evaluation will be a clinical examination and will include an assessment of the patient’s psychiatric and physical status and associated health parameters including vital signs, and status of any treatment emergent AEs.Atorney Ref: 42790-62103 (007WO1)Follow-Up Period:

[0107] Efficacy and safety assessments will be performed periodically during the study (FIGs.2A-2B).

[0108] The primary efficacy measure, the MADRS, will be 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+), C-SSRS, and CGI-S / Clinical Global Impression-Improvement (CGI-I) will also be completed.

[0109] Two integration sessions will be conducted, one as a part of the follow-up procedures on Day 1 and the other on Day 7. Efficacy ratings will be completed prior to each integration session.Study Arms and Duration:

[0110] Arm 1: Compound 1 administered by SC injection in the upper arm at a single dose of 30 mg (1.0 mL).[oni] Arm 2: Compound 1 administered by SC injection in the upper arm at a single dose of 1.5 mg (0.05 mL).

[0112] The low compound 1 dose arm (Arm 2) will be used as a control rather than placebo to minimize the likelihood of functional unblinding of site staff and patients and is common in psychedelic clinical trials.

[0113] The study duration for each patient will be up to 53 days including an up to 21 -day screening window.5.1.2. Patient PopulationInclusion Criteria

[0114] Patients are eligible to be included in the study only if all of the following criteria apply:Atorney Ref: 42790-62103 (007WO1)1. Is female aged 18 to 45 years, inclusive, at the time of signing the Informed Consent Form (ICF).2. Is <15 months postpartum at Screening and meets 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. Has a HAMD-17 total score of >24 at Screening and Baseline (Day -1 prior to dosing). 4. Is not currently receiving and is willing to delay the use of any psychotropic pharmacotherapy regimens (including antidepressant or antianxiety medication), and / or psychotherapy (unless on already a stable, established regimen of SSRIs and / or psychotherapy for 30 days prior to Screening) until Day 7 study assessments have been completed. Patients should not discontinue current, adequate psychotropic treatment(s) for the sole purpose of enrollment into the study.5. Has ceased breastfeeding at Screening (i.e., must have already fully and permanently weaned their infant[s] from breastfeeding).6. Is using an effective and appropriate method of contraception at Screening and agrees to continue to use such a method throughout the duration of the study. The method of contraception agreed to must be documented for each patient.7. Has a negative pregnancy test at Screening and Day 0 prior to study drug administration. 8. Is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.9. Is willing and able to nominate a trusted caregiver who:a. Can 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. Agrees to adhere to the study requirements.Exclusion Criteria

[0115] Patients are excluded from the study only if any of the following criteria apply:Atorney Ref: 42790-62103 (007WO1)History or active postpartum psychosis per Investigator assessment.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.Has a significant risk of suicide according to the C-SSRS at Screening or Baseline (Day -1) or has attempted suicide within 12 months prior to the Screening Visit.a. Acute suicidality as evidenced by answering “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. History of suicidal behavior such that a determination of “yes” is 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.”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. 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.Active or medical history of seizures other than childhood febrile seizures.A positive CO VID-19 antigen test within 14 days of Treatment Day 0.Has 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).Atorney Ref: 42790-62103 (007WO1)Exposure to another clinical study involving study treatment within 30 days prior to Screening.Administration of electroconvulsive therapy (ECT) or transcranial magnetic stimulation within 90 days prior to Screening and / or plans to administer ECT before the Study Day 28 Visit.Use of psychedelics such as psilocybin, ayahuasca, mescaline, or LSD (with the exception of cannabis) within 12 months prior to Screening.Initiated new psychotherapy (cognitive behavioral therapy) within 30 days prior to Screening. No changes to stable psychotherapy, within 30 days prior to Screening.se of prohibited medications / agents as listed in Table 3.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.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 may not exclude a patient if, after discussion with and evaluation by the Investigator, the patient agrees not to use any marijuana or other cannabinoid products during the study, and if allowed to participate, the patient must test negative for cannabinoids on Day 0. Any positive urine drug test will be reviewed with patients to determine the pattern of use and eligibility will be determined at the Investigator’s discretion in conjunction with the Medical Monitor.Patient who, as determined by the Investigator, is 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 RE 104).Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.Atorney Ref: 42790-62103 (007WO1)Lifestyle Considerations

[0116] On the day of dosing, patients should have a light snack no later than 2 hours prior to dosing. A light meal will be available to patients towards the end of the dosing session (approximately 4-5 hours after dosing).

[0117] Patients should limit ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before the administration of study drug (e.g., limit to no more than 1 cup of coffee on day of dosing).

[0118] Patients should abstain from alcohol for 24 hours before the administration of study drug and limit use of the alcohol to no more than 1 unit of alcohol per day during participation in the study.

[0119] Patients who use tobacco products will be instructed that use of such products will not be permitted throughout the dosing session and until clinic discharge.5.1.3. Study Interventions

[0120] The drug product is a sterile lyophilized solid supplied in a single use vial ready for reconstitution with an aqueous sterile diluent (Table 1).Table 1. Study Interventions AdministeredAtorney Ref: 42790-62103 (007WO1)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 1.6 mg / mL compound 1 (HC1 salt).

[0121] The diluent, which is composed of sodium phosphate dibasic and sodium chloride, is used to solubilize and neutralize the HC1 salt when 1.1 mL of the diluent is added to the content of the vial, thereby producing compound 1 (zwitterion). The resulting solution has a pH between 4.5 to 5.5 and is ready for injection as a 30 mg / mL free base (equivalent to 33 mg / mL HC1 salt).5.1.3.1 Prior and Concomitant Therapy

[0122] All medications (prescription and over-the-counter [OTC]) taken within 30 days of study Screening will be recorded along with reason for use, dates of administration, and dosage information (including dose and frequency). In addition, all historic use of psychedelic drugs will be recorded and all psychiatric medications taken within the last 2 years prior to Screening will be recorded.

[0123] All medications (prescription and OTC) taken starting from the study Screening Period through End of Study will be recorded along with reason for use (e.g., worsening of PPD symptoms), dates of administration, and dosage information (including dose and frequency).Atorney Ref: 42790-62103 (007WO1)

[0124] Patients with worsening of symptoms as defined below may start treatment with antidepressants if needed after Day 7:• Patient is 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 report suicidal ideation or behavior per the Investigator judgment should be referred for appropriate medical care— OR—• CGI-I scores at Day 7 of 6 (much worse) or 7 (very much worse)—OR—• Is warranted for patient safety, in the opinion of the Investigator.

[0125] The medications described in Table 2 are prohibited within the timeframes indicated. Note that a full listing of other drugs with the potential to precipitate serotonin-related adverse reactions (which are excluded within 28 days prior to Screening) are provided as in Table 3.Atorney Ref: 42790-62103 (007WO1)Table 2. Prohibited Medications>Note for items in italics'. Episodic, low dose use of these listed medications for conditions, that otherwise do not exclude patients from participating in the study, may be allowed during the 28 days prior to Screening provided that:• The investigator has obtained sufficient information from the patient to confirm the dosage, reason, frequency and pattern of use as infrequent / occasional• The patient agrees to not use the medication during the study• The investigator has obtained Sponsor and / or Study Medical Monitor approval in support of eligibility (provided that no other eligibility issues are present)Atorney Ref: 42790-62103 (007WO1)Table 3. Agents that Alone or in Conjunction with Other Serotonergic Agents Can Precipitate Serotonin-related Adverse ReactionsAtorney Ref: 42790-62103 (007WO1)5.1.4. Study Procedures

[0126] Study procedures and their timing are summarized in the SoA (FIGs.2A-B) and below.Screening Period (Visit 1)

[0127] An ICF must be signed by patients before any study-related assessments are performed. Eligibility will be determined during the Screening Period (up to 3 weeks [Days -21 to -2]) and confirmed through a central Eligibility Review conducted by the Study Medical Monitor and the Study Clinical Assessment Technologies (CAT) Clinician prior to Day 0.

[0128] At the initial Screening Visit (VI), assessments will be performed by the designated site staff as noted below. Diagnosis of PPD will be 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 will not serve as the blinded independent rater for the study. The patient will also complete the first of 2 preparatory sessions, lasting approximately 30-60 minutes in person with a qualified Session Monitor. The preparatory sessions are to prepare and educate patients about dosing and post-dosing experiences and their management, as applicable.Baseline Period (Visits 2 and 3)

[0129] The Baseline Period should begin within about 3 weeks of Screening and is split over 2 visits, with assessments occurring at Day -1 (Visit 2) and prior to dosing on Day 0. Patients will be contacted remotely at Day -1 then return to the clinic for pre-dose assessments on the day of dosing. The second preparatory session will be scheduled as a part of Visit 2 procedures and may be completed remotely with the LSM. Assessments to be completed at Day -1 must be completed within a 4-day window of dosing on Day 0 to allow for adequate time for confirmation ofAtorney Ref: 42790-62103 (007WO1)eligibility by the Investigator. Dosing should not proceed until eligibility is confirmed based on results obtained and assessments completed after Screening.

[0130] Baseline Day 0 (Visit 3, pre-dose in-clinic): Baseline MADRS ratings on Day 0 should be completed prior to any other efficacy assessments by a blinded, independent rater who is able to consistently rate the patient throughout the study. Patients will be reminded of the importance of reporting their symptoms accurately prior to completion of the MADRS through use of a standardized script. Patients should not be randomized until availability of the assigned appropriate LSM and Assistant Session Monitor (ASM) have been confirmed on the day of dosing.Treatment Period (Visit 3; 0 to 8 hours)

[0131] Dosing with study medication will occur on Day 0 after all pre-dose assessments and procedures have been completed. The study drug will be prepared and administered as an subcutaneous (SC) injection by an unblinded pharmacist, nurse, or other appropriately trained and qualified designee.

[0132] After dosing, patients will remain 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.

[0133] To ensure that compound 1 effects have fully subsided, patients will be assessed for safety and discharge readiness by a medically qualified Investigator or designee.

[0134] At the 8-hour post-dose timepoint and once deemed ready for discharge, patients will be allowed to go home and must be escorted by a trusted friend or family member, or caregiver. The session monitor and / or medically qualified Investigator or designee will check in with the patient (and / or family member etc. if applicable) later in the evening to confirm that the patient is comfortable and stable.

[0135] If the patient’s clinical condition does not warrant discharge at the 8-hour post-dose timepoint, the patient will be managed under standard of care until ready for discharge and confirmed by a medically qualified Investigator.

[0136] Assessments will be performed as per the SoA.Follow-up Period (Visits 4 to 10)Atorney Ref: 42790-62103 (007WO1)

[0137] The 28-day Follow-Up Period will include 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 2 integration sessions. For efficacy assessments, the MADRS should be completed first by the blinded independent rater, preceded by a reminder of the importance of reporting their symptoms accurately through use of a standardized script. Remote safety check-ins will also occur at Day 4, 10, and 21 as specified in the SoA.5.1.5. Efficacy Assessments5.1.5.1 Mon tgom ery- sbe rg Depression Rating Scale (MADRS)

[0138] The MADRS is a validated 10-item questionnaire to assess depression severity and is commonly used to assess efficacy of an intervention in clinical trials. Each item of the MADRS is measured on a scale of 0 to 6 (for a total score of 0 to 60) with higher scores indicating more severe depression. The MADRS will be administered using 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 will be preceded by a standardized Reminder Script reminding patients to report their symptoms accurately at each timepoint in order to reduce potential “placebo” response.

[0139] The past week version of MADRS will be administered. For visits where the visit window requires it, a modified ‘since last evaluation’ version of the assessment will be used.5.1.5.2 Hamilton Rating Scale for Depression (HAMD-17)

[0140] 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 will be used to confirm symptoms severity for study entry; it is not considered an efficacy measure.5.1.5.3 Clinical Global Impression-Improvement (CGI-I) and Clinical Global Impression-Severity (CGI-S)

[0141] The Clinical Global Impression Scale is a clinician-rated instrument comprised of 3 global measures: severity of illness, global improvement, and efficacy index.Atorney Ref: 42790-62103 (007WO1)

[0142] 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: l=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.”

[0143] 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).5.1.5.4 Hamilton Rating Scale for Anxiety (HAM-A)

[0144] The HAM-A is a 14-item scale that is used to rate the severity of symptoms of anxiety. Each of the 14 items is defined by a series of symptoms and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Items are scored from 0 (not present) to 4 (very severe), for a total score ranging from 0 to 56. Scores <17 indicate mild anxiety, scores of 18 to 24 indicate mild to moderate anxiety, and scores of 25 to 30 or higher indicate moderate to severe anxiety. The Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) will be used for this study.5.1.5.5 Structured Clinical Interview for DSM-5 Axis I Disorders (Clinical Trial Version)

[0145] The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for making major DSM-5 diagnoses. The SCID-5 is administered by a clinician or trained mental health professional who is 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.5.1.5.6 Edinburgh Postnatal Depression Scale

[0146] 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) are likely to be suffering from depression.Atorney Ref: 42790-62103 (007WO1)5.1.5.7 Patient Health Questionnaire-9 (PHQ-9)

[0147] 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’ve “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.

[0148] Each “not at all” response is scored as 0; each “several days” response is 1; each “more than half the days” response is 2; and each “nearly every day” response is 3. The sum value of these responses provides the total score with a higher score indicating more severe depression.5.1.5.8 Barkin Index of Maternal Functioning

[0149] 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.5.1.5.936- Item Short Form Survey

[0150] The 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.Atorney Ref: 42790-62103 (007WO1)5.1.5.10 Placebo-Control Reminder Script (PCRS)

[0151] The Placebo-Control Reminder Script (PCRS)(© Hassman and Cohen, 2019, Version 5.0) educates clinical trial participants of key causes of the placebo and nocebo effects, namely the tempering of participant study expectations, reminding subjects what a placebo is and how that relates to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differ from their experience with previous providers. To do this, the PCRS informs subjects that they are to be honest about their symptoms, site staff have no expectations of symptom improvement or worsening and will not be disappointed if they feel better, worse or the same, and asks participants to explain in their own words its content to ensure comprehension. Per the instructions on the PCRS, the efficacy scale rater will read the script verbatim immediately before administering efficacy scale. The PCRS is read to each subject at each visit (time point) as listed in the SOA, typically taking about 3 minutes to read. The PCRS has been empirically found to significantly manage (reduce) the placebo and nocebo effects.

[0152] In this study, the active control arm (low dose, 1.5 mg compound 1) is considered similar to a placebo in that it is being used to minimize the likelihood of functional unblinding of site staff and study participants. The PCRS will be modified as necessary to help reduce participant expectation bias in receiving the low dose (similar to a placebo).5.1.5.11 Other Assessments5.1.5.11.1 Mystical Experience Questionnaire

[0153] 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)• Positive mood• Transcendence of time and space• fneffabilityAtorney Ref: 42790-62103 (007WO1)

[0154] Patients will be asked to rate each item of the MEQ-4 on a 6-point scale.5.1.5.11.2 Challenging Experience Questionnaire

[0155] 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 are 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 is expressed as the percentage of the total possible ratings on the scale.5.1.5.11.3 Blinding Assessment

[0156] The adequacy of the blind will be 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. l 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. l am positive I received the lower dose of study drug.5.1.5.11.4 Suicidal Ideation and Behavior Risk Monitoring

[0157] Patients should be monitored appropriately and observed closely for suicidal ideation and behavior or any other unusual changes in behavior. Patients who experience signs of suicidal ideation or behavior should undergo a risk assessment.

[0158] When informed consent has been given, families and caregivers of patients being treated should be alerted about 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.

[0159] Baseline assessment of suicidal ideation and behavior will be monitored during the Follow-Up Period using the Columbia-Suicide Severity Rating Scale (C-SSRS). The “baseline / screening” version will be administered at Screening and Day -1 (since the purpose of application at these time points is to exclude patients with suicidal ideation prior to dosing) andAtorney Ref: 42790-62103 (007WO1)the “since last visit” version will be administered thereafter (since the purpose of the application at these timepoints are to monitor patients after dosing has started).

[0160] The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item scale. The C- SSRS also captures information about the intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons for the most severe types of ideation. In addition, the C-SSRS captures information using yes / no questions and answers on suicidal behavior, specifically actual, interrupted, and aborted attempts; preparatory acts or behavior; and if suicidal behavior was present during the assessment period. For actual attempts only, the actual or potential lethality is classified for the initial, most lethal, and most recent attempts.5.1.5.11.5 Monitoring for Psychosis

[0161] Patients will be monitored for the presence of psychosis after the dosing session during the Follow-Up Period using the BPRS+. The BPRS+ is a 4-item, clinician administered subscale of the 18-item BPRS, used to assess symptoms of psychosis, anxiety, and depression. The 4-item positive symptom subscale assesses hallucinations, unusual thought content, suspiciousness, and conceptual disorganization, scored on a scale from 1 (not present) to 7 (extremely severe) with a score range of 4 to 28. A score of 0 is recorded if the symptom is not assessed.5.1.5.11.6 Assessment of Injection Site Reactions

[0162] Following administration of study drug, the location of the SC injection will be evaluated to determine if there were any local changes to the area surrounding the injection site per the SoA. If findings are observed, a detailed description of the events should be included in the source documentation and appropriate AE term included in the case report form.5.1.5.11.7 Discharge Readiness Assessment

[0163] The post-dose discharge readiness evaluation will be a clinical examination which will include an assessment of the patient’s psychiatric and physical status and associated health parameters including vital signs and status of any treatment emergent AEs. Discharge readiness review will be performed between the 4-hour and 8-hour post-dose timepoint, and as per the SoA.Atorney Ref: 42790-62103 (007WO1)

[0164] At the time of the 8-hour assessment and prior to discharge, patients must be: (1) fully ambulatory with good balance; (2) have confirmed cardiovascular parameters, including stable vital signs, within normal limits or not clinically significantly elevated compared to baseline; and (3) be psychologically stable, 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) must be resolved or stable and not clinically significant at time of discharge.

[0165] The patient must not be discharged prior to 8-hours post-dose (regardless of prior documented “readiness”). If the patient’s clinical condition does not warrant discharge at the 8-hour post-dose timepoint, the patient will be managed under standard of care until ready for discharge and confirmed by a medically qualified Investigator.5.1.6. Adverse Events, Serious Adverse Events, and Other Safety Reporting

[0166] 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.

[0167] An AE or suspected adverse reaction is considered “serious” if, in the view of either the Investigator or Sponsor, it results in any of the following outcomes:• Death (death should be recorded as the outcome and the initiating event leading to death as the event)• Life-threatening (i.e., immediate risk of death from the event as it occurred; this does not include an AE that, had it occurred in a more serious form, might have caused death)• Persistent or significant disability / incapacitation• Inpatient hospitalization or prolongation of existing hospitalization• Congenital anomaly / birth defect

[0168] Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE reporting is appropriate in other situations such as significant medical events thatAtorney Ref: 42790-62103 (007WO1)may jeopardize the patient or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should usually be considered serious.

[0169] The study will demonstrate safety and efficacy of compound 1 in treating PPD.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0170] 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.

[0171] 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.

Claims

Atorney Ref: 42790-62103 (007WO1)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:or 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 was diagnosed with PPD prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.Atorney Ref: 42790-62103 (007WO1)7. The method according to claim 6, wherein the subject was 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 claim 6 or claim 7, wherein the subject had a Hamilton Rating Scale for Depression (HAMD-17) score of at least 24 when the subject was evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

9. The method according to any one of claims 6-8, wherein the subject had 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.

10. The method according to any one of claims 4-9, wherein the subject has been on a stable regimen of SSRIs for at least 30 days prior to administration of compound 1.

11. The method according to any one of claims 4-9, wherein the subject has been on a stable psychotherapy regimen for at least 30 days prior to administration of compound 1.

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

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

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

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

16. The method according to claim 15, wherein the subject remains in the medical facility for at least 8 hours following administration of compound 1.

17. The method according to any one of the preceding claims, wherein compound 1 is administered to the subject by a medically trained professional.

18. 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),Atorney Ref: 42790-62103 (007WO1)such as 30 mg (free base) or 33 mg (HC1 salt).

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

20. The method according to claim 19, wherein the single dose is in the form of a solution.

21. The method according to any one of the preceding claims, wherein compound 1 isadministered to the patient as the zwitterion(1).

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

23. The method according to claim 22, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

24. The method according to any one of claims 3-23, 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).

25. The method according to any one of claims 3-24, wherein the subject’s Montgomery- Asberg Depression Rating Scale (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).

26. The method according to claim 25, 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 MARDS 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).

27. The method according to claim 26, wherein the subject’s MARDS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.Atorney Ref: 42790-62103 (007WO1)28. The method according to claim 25, wherein the subject’s MADRS score is 10 or less following administration of compound 1.

29. The method according to claim 27, wherein the subject has a MADRS score of 10 or less 7 days after administration of compound 1 (Day 7).

30. The method according to any one of claims 3-29, wherein the subject’s Clinical Global Impression-Improvement (CGI-I) score demonstrates improvement in depressive symptoms following administration of compound 1.

31. The method according to claim 30, wherein the subjects CGI-I score is 3 or less, such as 3, 2 or 1.

32. The method according to claim 30 or claim 31, 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).

33. The method according to any one of claims 3-32, 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).

34. The method according to claim 33, 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.

35. The method according to claim 33 or claim 34, 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).

36. The method according to any one of claims 3-35, 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).

37. The method according to claim 36, 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).Atorney Ref: 42790-62103 (007WO1)38. The method according to claim 37, wherein the subject’s HAM-A score is less than 30, preferably less than 25.

39. The method according to claim 37 or 38, 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).

40. 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 compound 1 is represented by:or is a zwitterion or a pharmaceutically acceptable salt thereof, wherein the subject (a) has been on a stable regimen of SSRIs 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.

41. The method of claim 40, 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.

42. The method according to claim 40 or 41, wherein the psychological disease or disorder is selected from depression, MDD, PPD, and drug-resistant depression.

43. The method according to claim 42, wherein the psychological disease or disorder is PPD.

44. The method according to claim 43, wherein the subject is no more than 15 monthspostpartum.Atorney Ref: 42790-62103 (007WO1)45. The method according to any one of claims 42-44, wherein the subject was diagnosed with PPD prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

46. The method according to claim 45, wherein the subject was 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).

47. The method according to claim 45 or claim 46, wherein the subject had a Hamilton Rating Scale for Depression (HAMD-17) score of at least 24 when the subject was evaluated prior to administration of compound 1, such as in the 21 days prior to administration of compound 1.

48. The method according to any one of claims 6-8, wherein the subject had 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.

49. The method according to any one of claims 40-48, wherein the subject has been on a stable regimen of SSRIs for at least 30 days prior to administration of compound 1.

50. The method according to claim 49, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

51. The method according to any one of claims 40-48, wherein the subject has been on established psychotherapy for at least 30 days prior to administration of compound 1.

52. The method according to claim 51, 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.

53. The method according to any one of claims 40-52, wherein compound 1 is administered by injection, such as subcutaneous injection.

54. The method according to any one of claims 40-53, wherein compound 1 is administeredAtorney Ref: 42790-62103 (007WO1)to the subject in a medical facility.

55. The method according to claim 54, wherein the subject remains in the medical facility for at least 8 hours following administration of compound 1.

56. The method according to any one of claims 40-55, wherein compound 1 is administered to the subject by a medically trained professional.

57. The method according to any one of claims 40-56, wherein compound 1 is administered in an amount from 20 to 60 mg (calculated as the free base or HC1 salt), such as 30 mg (free base) or 33 mg (HC1 salt).

58. The method according to any one of claims 40-57, wherein compound 1 is administered as a single dose.

59. The method according to claim 58, wherein the single dose is in the form of a solution.

60. The method according to any one of claims 40-59, wherein compound 1 is administeredto the patient as the zwitterion61. The method according to any one of claims 42-60, 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).

62. The method according to any one of claims 42-60, wherein the subject’s Montgomery- Asberg Depression Rating Scale (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).

63. The method according to claim 62, 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 MARDS 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, DayAtorney Ref: 42790-62103 (007WO1)14, and Day 28).

64. The method according to claim 63, wherein the subject’s MARDS score on Day 7 is reduced by at least 50% compared to the subject’s MADRS score on Day 0.

65. The method according to claim 62, wherein the subject’s MADRS score is 10 or less following administration of compound 1.

66. The method according to claim 65, wherein the subject has a MADRS score of 10 or less 7 days after administration of compound 1 (Day 7).

67. The method according to any one of claims 42-66, wherein the subject’s Clinical Global Impression-Improvement (CGI-I) score demonstrates improvement in depressive symptoms following administration of compound 1.

68. The method according to claim 67, wherein the subjects CGI-I score is 3 or less, such as 3, 2 or 1.

69. The method according to claim 67 or claim 68, 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).

70. The method according to any one of claims 42-69, 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).

71. The method according to claim 70, 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.

72. The method according to claim 70 or claim 71, 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).

73. The method according to any one of claims 42-72, 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).Atorney Ref: 42790-62103 (007WO1)74. The method according to claim 73, 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).

75. The method according to claim 74, wherein the subject’s HAM-A score is less than 30, preferably less than 25.

76. The method according to claim 74 or 75, 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).

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