Patient specific methods of treating neuropsychiatric disorders with non-hallucinogenic tryptamines

Abstract

Disclosed herein are compounds, compositions, and methods for promoting neuronal growth and / or improving neuronal structure with the compounds and compositions disclosed herein. Also described are methods of treating diseases or disorders that are mediated by the loss of synaptic connectivity and / or plasticity, such as neurological diseases and disorders, with non-hallucinogenic psychoplastogens.

Description

WSGR Docket No. 55776-729.601PATIENT SPECIFIC METHODS OF TREATING NEUROPSYCHIATRIC DISORDERS WITH NON-HALLUCINOGENIC TRYPTAMINESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 679,470, filed on August 5, 2024; US Provisional Application No. 63 / 729,838, filed on December 9, 2024; and US Provisional Application No. 63 / 809,675, filed on May 21, 2025; each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders that would benefit from promoting neuronal growth and / or improving neuronal structure.BACKGROUND OF THE INVENTION

[0003] Altered synaptic connectivity and plasticity has been observed in the brains of individuals with neurological diseases and disorders. Psychoplastogens promote neuronal growth and improve neuronal architecture through mechanisms involving the activation of AMPA receptors, the tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR). Modulators of these biological targets, such as, for example, ketamine, scopolamine, N,N- dimethyltryptamine (DMT), and rapastinel have demonstrated psychoplastogenic properties. For example, ketamine is capable of rectifying deleterious changes in neuronal structure that are associated with neurological diseases and disorders. Such structural alterations include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC) as well as reductions in dendritic arbor complexity. Furthermore, pyramidal neurons in the PFC exhibit top- down control over areas of the brain controlling motivation, fear, and reward. Psychedelic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti -addictive effects of in the clinic.SUMMARY OF THE INVENTION

[0004] Due to the limitations of psychedelic psychoplastogens, including dissociative effects and strain on clinical resources, new non-hallucinogenic therapeutic options are needed to treat neuropsychiatric disorders.WSGR Docket No. 55776-729.601

[0005] In one aspect, provided herein is a method of treating a neuropsychiatric disease in an individual in need thereof, comprising administering to the individual about Img to about 500 mg of Compound 1 calculated by free base:Compound 1.In some embodiments, the individual has a cytochrome P450 2D6 (CYP2D6) activity score (AS). The CYP2D6 AS may be classified as low, intermediate, or high. In some embodiments, the neuropsychiatric disease is depression, addiction, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the neuropsychiatric disease is depression, or anxiety. In some embodiments, the neuropsychiatric disease is depression. In some embodiments, the neuropsychiatric disease is treatment resistant depression, major depressive disorder, suicidal ideation, or combinations thereof. In some embodiments, the neuropsychiatric disease is major depressive disorder.

[0006] In some embodiments, the individual has a low AS. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25. In some embodiments, the individual has a low AS selected from 0.25, 0.5, and 0.75. In some embodiments, the individual has a low AS of 0.25. In some embodiments, the individual has a low AS of 0.5. In some embodiments, the individual has a low AS of 0.75. In some embodiments, the individual has a low AS and is administered a dose of about 50 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 60 mg to 90 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 60 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 75 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 80 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 90 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered a dose of about 100 mg of Compound 1 calculated by free base.

[0007] In some embodiments, the individual has an intermediate AS. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25. In some embodiments, the individual has an intermediate AS selected from 0.5, 0.75, 1.0, 1.25, and 1.5. In some embodiments, the individual has an intermediate AS from 0.5 to 1.25. In some embodiments, theWSGR Docket No. 55776-729.601 individual has an intermediate AS selected from 0.5, 0.75, 1.0, and 1.25. In some embodiments, the individual has an intermediate AS of 0.5. In some embodiments, the individual has an intermediate AS of 0.75. In some embodiments, the individual has an intermediate AS of 1.0. In some embodiments, the individual has an intermediate AS of 1.25. In some embodiments, the individual has an intermediate AS of 1.5. In some embodiments, the individual has an intermediate AS and is administered a dose of about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 120 mg to 180 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 120 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 160 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered a dose of about 180 mg of Compound 1 calculated by free base.

[0008] In some embodiments, the individual has a high AS. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25. In some embodiments, the individual has a high AS selected from 1.25, 1.5, 1.75, 2.0, and 2.25. In some embodiments, the individual has a high AS from 1.5 to 2.25. In some embodiments, the individual has a high AS selected from 1.5, 1.75, 2.0, and 2.25. In some embodiments, the individual has a high AS of 1.25. In some embodiments, the individual has a high AS of 1.5. In some embodiments, the individual has a high AS of 1.75. In some embodiments, the individual has a high AS of 2.0. In some embodiments, the individual has a high AS of 2.25. In some embodiments, the individual has a high AS and is administered a dose of about 200 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 220 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 240 mg to 360 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 240 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 250 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 300 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 350 mg ofWSGR Docket No. 55776-729.601Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered a dose of about 360 mg of Compound 1 calculated by free base.

[0009] In one aspect, provided herein is a method of treating a neuropsychiatric disease in an individual in need thereof, comprising administering to the individual Compound 1:Compound 1, wherein the individual has a cytochrome P450 2D6 (CYP2D6) activity score (AS). The CYP2D6 AS may be classified as low, intermediate, or high. In some embodiments, the individual has a high AS and Compound 1 is administered at a maximum tolerated dose of Compound 1 . In some embodiments, the individual has an intermediate AS and Compound 1 is administered at a one-half maximum tolerated dose of Compound 1. In some embodiments, the individual has a low AS and Compound 1 is administered at a one-quarter maximum tolerated dose of Compound 1. In some embodiments, the individual has a high AS and Compound 1 is administered at a high dose of Compound 1. In some embodiments, the individual has an intermediate AS and Compound 1 is administered at an intermediate dose of Compound 1. In some embodiments, the individual has a low AS and Compound 1 is administered at a low dose of Compound 1. In some embodiments, the individual has a high AS and the maximum tolerated dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS and the high dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the one-half maximum tolerated dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the intermediate dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the one-half maximum tolerated dose of Compound 1 is about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the intermediate dose of Compound 1 is about 125 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, or about 180 mg calculated by free base. In someWSGR Docket No. 55776-729.601 embodiments, the individual has a low AS and the one-quarter maximum tolerated dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, or about 90 mg calculated by free base. In some embodiments, the individual has a low AS and the low dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the maximum tolerated dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the high dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the one-half maximum tolerated dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the intermediate dose of Compound 1 is about 125 mg, about 150 mg, about 160 mg, about 170 mg about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25 and the one-quarter maximum tolerated dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, or about 90 mg calculated by free base. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25 and the low dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg calculated by free base. In some embodiments, the individual has a high AS and is administered 200 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 220 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 240 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 250 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 300 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 350 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 360 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 120 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 150 mg of Compound 1 calculated by free base. In some embodiments,WSGR Docket No. 55776-729.601 the individual has an intermediate AS and is administered about 160 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 180 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 50 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 60 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 75 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 80 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 90 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.25 and is administered a dose of about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to 0.75 and is administered a dose of about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to 1.25 and is administered a dose of about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to1.25 and is administered a dose of about 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 1.0 to 2.25 and is administered a dose of about 250 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 1.5 to2.25 and is administered a dose of about 250 mg of Compound 1 calculated by free base. In some embodiments, the neuropsychiatric disease is depression, addiction, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the neuropsychiatric disease is depression. In some embodiments, the neuropsychiatric disease is treatment resistant depression, major depressive disorder, suicidal ideation, or combinations thereof. In some embodiments, the neuropsychiatric disease is major depressive disorder.

[0010] In one embodiment, Compound 1 is administered to the individual orally. In some embodiments, Compound 1 is administered to the individual at a dose of about 1 mg to about 500 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 1 mg to about 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 1 mg to about 10 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 2 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 6 mg calculated by free base. In some embodiments, Compound 1 is administered toWSGR Docket No. 55776-729.601 the individual at a dose of about 10 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual a dose of about 10 mg to about 30 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 20 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 30 mg to about 100 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 60 mg to about 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 50 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 60 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 75 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 80 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 100 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 100 mg to about 240 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 120 mg to about 180 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 120 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 150 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 160 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 170 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 180 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 200 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 220 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg to about 500 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg to about 360 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 300 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 350 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 360 mgWSGR Docket No. 55776-729.601 calculated by free base. In some embodiments, Compound 1 is administered once per day. In some embodiments, Compound 1 is administered once every 2 days. In some embodiments, Compound 1 is administered once every 3 days. In some embodiments, Compound 1 is administered 1 time per week. In some embodiments, Compound 1 is administered 2 times per week. In some embodiments, Compound 1 is administered 3 times per week.

[0011] In one embodiment, administering Compound 1 to the individual does not cause hallucinations, dissociative effects, or psychomimetic effects. In some embodiments, Compound 1 is non-hallucinogenic, non-dissociative, and non-psychomimetic. In some embodiments, administering Compound 1 to the individual does not cause hallucinations, dissociative effects, or psychomimetic effects as determined by a Clinician-Administered Dissociative States Scale (CDSS), a Bond-Lader Visual Analog Scale (VAS), a Bowdle VAS, or a Revised Mystical Experience Questionnaire (MEQ-30), or a combination thereof.

[0012] In one embodiment, Compound 1 achieves a Cmax under about 10 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a Cmax under about 5 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a Cmax at about 2 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a CSF / Plasma Ratio of about 0.10 to about 0.50, or of about 0.15 to about 0.30, or of about 0.20. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 10 ng / mL to about 1,000 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 25 ng / mL to about 500 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 50 ng / mL to about 360 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 180 ng / mL to about 360 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 50 ng / mL to about 250 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 100 ng / mL to about 250 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 75 ng / mL to about 125 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a CmaXof about 100 ng / mL in the individual.

[0013] In one aspect, disclosed herein is a pharmaceutical composition comprising about 1 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, disclosed herein is aWSGR Docket No. 55776-729.601 pharmaceutical composition comprising 1 mg to 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 250 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 2 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 6 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 30 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 30 mg to about 100 mg of Compound 1 calculated by free base. In some embodiments the pharmaceutical composition comprises about 50 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 60 mg to about 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 75 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 250 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 240 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 120 mg to about 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 120 of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 250 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg toWSGR Docket No. 55776-729.601 about 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0014] In one embodiment, described herein is a method of promoting neuronal growth in an individual comprising administering to the mammal Compound 1. In another embodiment, described herein is a method of improving neuronal structure comprising administering to the individual Compound 1. In another embodiment, described herein is a method of modulating the activity of 5-hydroxytryptamine receptor 2A (5-HT2A) receptor in an individual comprising administering to the individual Compound 1. In another embodiment, described herein is a method of treating a disease or disorder in an individual that is mediated by the action of 5- hydroxytryptamine (5-HT) at 5-hydroxytryptamine receptor 2A (5-HT2A) comprising administering to the individual Compound 1. In another embodiment, described herein is a method of treating a disease or disorder in an individual that is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof comprising administering to the individual Compound 1. In some embodiments, the disease or disorder is neurological disease or disorder. In some embodiments, the disease or disorder is depression, addiction, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the neuropsychiatric disease is depression. In some embodiments, the disease or disorder is treatment resistant depression, major depressive disorder, suicidal ideation, or combinations thereof. In some embodiments, the disease or disorder is major depressive disorder.

[0015] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF DRAWINGS

[0016] FIG. 1A-1C illustrates that Compound 1 promotes structural plasticity in vitro. FIG. 1A illustrates the processes for a rat cortical neurite outgrowth assay. FIG. IB illustrates an increase in neurite differentiation for Compound 1 treated cortical neurons compared to control. FIG. 1C illustrates changes in neurite length with Compound 1 treatment.WSGR Docket No. 55776-729.601

[0017] FIG. 2A-2E illustrate that Compound 1 produced rapid and enduring antidepressant-like effects. FIG. 2A illustrates rapid antidepressant -like activity after a single IP injection of Compound 1 24 hours before testing in a rat forced swim test. FIG. 2B illustrates that antidepressant-like effects of Compound 1 were durable and remained observable 7-days post administration in a rat forced swim test. FIG. 2C illustrates that antidepressant-like effects of Compound 1 were observed 24 hours after oral administration in a rat forced swim test. *p<0.05 one-way ANOVA. Dunnett’s post-hoc test. FIG. 2D illustrates that antidepressant like effects of Compound 1 were observed 30 minutes after administration in a mouse tail suspension test. FIG. 2E illustrates Compound 1 reversed a stress-induced social deficit in mouse chronic social defeat. C57BL / 6 mice exposed to aggressors for 10 days were assessed for social preference of a novel conspecific. Stress susceptible mice (left bars) and were administered vehicle, ketamine, psilocybin, or Compound 1 and assessed a second time for their social preference (right bars). *p<0.05 one-way ANOVA. Dunnett’s post-hoc test for FIG. A-D. *p<0.05 two-model ANOVA Sidak’s multiple comparison test (pre vs post dose) for FIG. E.

[0018] FIG. 3 illustrates that Compound 1 achieves high plasma and brain levels following oral administration in multiple species.

[0019] FIG. 4A-4B. illustrates that Compound 1 does not produce head twitches in rodents. FIG. 4A illustrates the number of head twitches in mice after administration of psilocybin, DOI, or Compound 1. FIG. 4B illustrates the number of head shakes in rats after administration of DOI or Compound 1.

[0020] FIG. 5A-5F illustrate that Compound 1 promotes structural plasticity in the PFC in vivo at behaviorally relevant doses. FIG. 5A illustrates an in vivo dendritic spinogenesis assay. FIG. 5B illustrates Golgi stained layer V PFC pyramidal neurons treated with 3, 10, or 30mg / kg Compound 1. FIG. 5C and 5D illustrate Compound 1 dose dependently induces spinogenesis in vivo. FIG. 5E and 5F illustrate psilocybin (PSI) and ketamine induce spinogenesis in vivo.

[0021] FIG. 6A-6F illustrate that Compound 1 increases functional plasticity in the PFC in vivo at behaviorally relevant doses. FIG. 6A illustrates an ex vivo functional plasticity assay. FIG. 6B illustrates pEPSC traces from layer V PFC pyramidal neurons treated with Vehicle or Compound 1. FIG. 6C illustrates the cumulative mean frequency of EPSCs recorded from mPFC lay er -V pyramidal neurons in rat brain slices treated with Vehicle or Compound 1. FIG. 6D illustrates the peak amplitude of EPSCs recorded from mPFC layer-V pyramidal neurons in rat brain slices treated with Vehicle or Compound 1. FIG. 6E illustrates the cumulative mean frequency of EPSCs recorded from mPFC layer-V pyramidal neurons in rat brain slices treated with Compound 1, DMT, ketamine, and psilocybin as a % of control. FIG. 6F illustrates the peak amplitude of EPSCsWSGR Docket No. 55776-729.601 recorded from mPFC layer-V pyramidal neurons in rat brain slices treated with Compound 1, DMT, ketamine, and psilocybin as a % of control.

[0022] FIG. 7 illustrates the study schematic of the human clinical trial.

[0023] FIG. 8 illustrates the sample characteristics of subjects enrolled in the clinical trial.

[0024] FIG. 9 illustrates the TEAEs by preferred term of subjects enrolled in the clinical trial.

[0025] FIGs. 10A-10B illustrate CADSS total score over time in subjects of the SAD cohort (FIG. 10A) and MAD cohort (FIG. 10B) respectively.

[0026] FIGs. 11A-11C illustrate bond and lader (B&L) visual analogue scale mean value over time in subjects of the SAD cohort (FIG. 11 A) and MAD cohort (FIG. 11B) respectively. FIG. 11C illustrates the B&L visual analogue scale.

[0027] FIGs. 12A-12D illustrate CADSS total score over time (FIG. 12A), derealization score over time (FIG. 12B), depersonalization score over time (FIG. 12C), and amnesia score over time (FIG. 12D) in subjects of the SAD cohort treated with 2 mg, 6 mg, 20 mg, 60 mg, 120 mg, 160 mg, 220 mg, or 360 mg of Compound 1.

[0028] FIGs. 13A-13D illustrate CADSS total score over time (FIGI. 13A , derealization score over time (FIG. 13B), depersonalization score over time (FIG. 13C), and amnesia score over time (FIG. 13D) in subjects of the MAD cohort treated with 50 mg, 100 mg, 120 mg, or 350 mg of Compound 1.

[0029] FIGs. 14A-14D illustrate summary pharmacokinetics of Compound 1 in plasma of subjects of the SAD (FIG. 14A), Food Effect (FIG. 14B) and MAD cohorts (FIGs. 14C and 14D).

[0030] FIG. 15 illustrates the CSF / Plasma ratio of Compound 1.

[0031] FIG. 16A-16D illustrate the change in slow wave activity (SWA) in delta and theta bands as the magnitude of change from baseline before and after administering Compound 1 to a human subject. FIG. 16A illustrates the change in delta band power after administering 2 mg, 6 mg, 20 mg, 60 mg, or 120 mg of Compound 1. FIG. 16B illustrates the change in theta band power after administering 2 mg, 6 mg, 20 mg, 60 mg, or 120 mg of Compound 1. FIG. 16C illustrates the change in delta band power in subjects from the SAD and MAD cohorts. FIG. 16D illustrates the change in theta band power in subjects from the SAD and MAD cohorts.

[0032] FIG. 17A and FIG. 17B illustrate pharmacokinetics profiles for patients administered 2 mg, 6 mg, 20 mg, 60mg, 120 mg, 160 mg, or 220 mg of Compound 1. FIG. 17A illustrates linear pharmacokinetics across cohorts, and FIG. 17B illustrates the level of intrasubject variability.

[0033] FIG. 18A illustrates a physiologically based pharmacokinetic model of Compound 1 metabolism in individuals with CYP2D6 activity scores of 0.5, 1 to 1.5, or 2. FIG. 18B illustrates dose normalized concentration of Compound 1 in the plasma of individuals treated with CompoundWSGR Docket No. 55776-729.6011. The dose normalized concentrations separate into three groupings where individuals have a CYP2D6 activity score of 0.5, 1 to 1.5, or 2.

[0034] FIG. 19 illustrates the dose-normalized concentration of Compound 1 administered to human subjects as a measure of individual CYP2D6 activity score.

[0035] FIG. 20 illustrates an exemplary study flow chart for the Phase II study.

[0036] FIG. 21 illustrates the correlation between MADRS change from baseline on Day 7 and the Cmax of Compound 1 on Day 1 in study participants from Cohort A. Each dot on the figure represents one unique participant.

[0037] FIG. 22 illustrates slow wave density as in study participants during NREM on the first night after receiving Compound 1 as measured by polysomnography. Data are presented as standard error of the mean.DETAILED DESCRIPTION OF THE INVENTION

[0038] The present disclosure provides a non-hallucinogenic compound useful for the treatment of a variety of neurological diseases and disorders, such as major depressive disorder, as well as increasing neuronal plasticity.

[0039] Psychedelic compounds promote structural and functional neural plasticity in key circuits, elicit therapeutic responses in multiple neuropsychiatric disorders, and produce beneficial neurological effects that can last for months following a single administration. Compounds capable of modifying neural circuits that control motivation, anxiety, and drug-seeking behavior have potential for treating neurological diseases and disorders that are mediated by the loss of synaptic connectivity and / or plasticity. Moreover, such compounds are likely to produce sustained therapeutic effects because, for example, of the potential to treat the underlying pathological changes in circuitry.

[0040] Slow wave activity (SWA) in the brain has been proposed as a measure of cortical synaptic strengthening, which plays a role in memory consolidation and neural plasticity. Certain psychedelics, including ketamine, show an increase in SWA characterized by oscillations in the delta (0.5-4 Hz) and theta (4-8 Hz) frequency bands (Duncan et al., 2013). Surprisingly, Compound 1 was discovered to increase magnitude of change from baseline in both delta and theta frequency band absolute power, indicating Compound 1 increases neural plasticity (FIGs. 16A-16D). In some embodiments, administering Compound 1 increases slow wave activity (e.g., delta band power or theta band power), by at least about lOpp, at least about 20pp, at least about 3 Opp, at least about 40pp, at least about 50pp, at least about 60pp, at least about 70pp, at least about 80pp, at least about 90pp, or at least about lOOpp between 1 to 24 hours after administering Compound 1. As used here, “pp” means “percentage points.” For example, 50% and 54% differ by 4pp. In some embodiments,WSGR Docket No. 55776-729.601 administering Compound 1 increases slow wave activity by 10pp-20pp. In some embodiments, administering Compound 1 increases slow wave activity by 15pp-25pp. In some embodiments, administering Compound 1 increases slow wave activity by 20pp-30pp. In some embodiments, administering Compound 1 increases slow wave activity by 25pp-35pp. In some embodiments, administering Compound 1 increases slow wave activity by 30pp-40pp. In some embodiments, administering Compound 1 increases slow wave activity by 35pp-45pp. In some embodiments, administering Compound 1 increases slow wave activity by 40pp-50pp. In some embodiments, administering Compound 1 increases slow wave activity by 55pp-65pp. In some embodiments, administering Compound 1 increases slow wave activity by 60pp-70pp. In some embodiments, administering Compound 1 increases slow wave activity by 65pp-75pp. In some embodiments, administering Compound 1 increases slow wave activity by 70pp-80pp. In some embodiments, administering Compound 1 increases slow wave activity by 75pp-85pp. In some embodiments, administering Compound 1 increases slow wave activity by 80pp-90pp. In some embodiments, administering Compound 1 increases slow wave activity by 95pp-95pp. In some embodiments, administering Compound 1 increases slow wave activity by 90pp-100pp. In some embodiments, the slow wave activity is Delta band power. In some embodiments, the slow wave activity is Theta band power.

[0041] In some embodiments, 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, e.g., DMT, LSD, and DOI, demonstrating the correlation of 5-HT2A agonism and the promotion of neural plasticity (Ly et al., 2018; Dunlap et al., 2020). However, the hallucinogenic and dissociative potential of such compounds has limited the use of these compounds in the clinic for neurological diseases, such as, for example, neuropsychiatric diseases. (Ly et al., 2018)

[0042] Cytochrome P450 2D6 (CYP2D6), a drug-metabolizing enzyme that is known to be highly polymorphic, is responsible for the oxidation and metabolism of a wide range of drugs, including antidepressants, antipsychotics, and psychoplastogens. CYP2D6activity can significantly impact the pharmacokinetics of these medications. Pharmacokinetic studies of Compound 1 surprisingly found that Compound 1 displays a linear concentration elimination curve across treatment cohorts (FIG. 17A), but displays high intersubject variability (FIG. 17B) due to genetic polymorphisms in the CYP2D6 enzyme (FIGs 18A, 18B, and 19). Individuals can be classified into poor or low metabolizers with low CYP2D6 activity (activity score 0 to 0.5±0.25), intermediate metabolizers with intermediate CYP2D6 activity (activity score 0.75±0.25 to 1.25±0.25), high metabolizers with high CYP2D6 activity (activity score 1.5±0.25 to 2.25), and ultra metabolizers (CYP2D6 activity score >2.25) based on their genetic variants and resultingWSGR Docket No. 55776-729.601 enzyme activity. Poor metabolizers have reduced or absent enzyme function, whereas ultra metabolizers have increased enzyme activity. Compound l is a substrate for CYP2D6. Clinical genotyping of CYP2D6 enables quantification of an individual’s CYP2D6 activity, ranging from no activity (Activity Score, AS=0) to increased function (AS>2.25) and offers the opportunity to optimize drug dose based on CYP2D6 activity status. In some embodiments, the dose and / or frequency of Compound 1 administered to an individual is adjusted in view of the individual’s CYP2D6 activity score (AS). For example, an individual with a higher AS may be administered a higher dose of Compound 1 and an individual with a lower AS may be administered a lower dose of Compound 1. In some embodiments, the individual has a high AS and Compound 1 is administered at a maximum tolerated dose of Compound 1. In some embodiments, the individual has an intermediate AS and Compound 1 is administered at a one-half maximum tolerated dose of Compound 1. In some embodiments, the individual has a low AS and Compound 1 is administered at a one-quarter maximum tolerated dose of Compound 1. In some embodiments, the individual has a high AS and Compound 1 is administered at a high dose of Compound 1. In some embodiments, the individual has an intermediate AS and Compound 1 is administered at an intermediate dose of Compound 1. In some embodiments, the individual has a low AS and Compound 1 is administered at a low dose of Compound 1. In some embodiments, the individual has a high AS and the maximum tolerated dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS and the maximum tolerated dose of Compound 1 is 200 mg, 220 mg, 240 mg, 250 mg, 300 mg, 320 mg, 350 mg, or 360 mg calculated by free base. In some embodiments, the individual has a high AS and the high dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS and the high dose of Compound 1 is 200 mg, 220 mg, 240 mg, 250 mg, 300 mg, 320 mg, 350 mg, or 360 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the one-half maximum tolerated dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the one-half maximum tolerated dose of Compound 1 is 100 mg, 110 mg, 120 mg, 125mg, 150 mg, 160 mg, 175 mg, or 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the intermediate dose of Compound 1 is about 125 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS and the intermediate dose of Compound 1 is 125mg, 150 mg, 160 mg, 170 mg,WSGR Docket No. 55776-729.601175 mg, or 180 mg calculated by free base. In some embodiments, the individual has a low AS and the one-quarter maximum tolerated dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, or about 90 mg calculated by free base. In some embodiments, the individual has a low AS and the one-quarter maximum tolerated dose of Compound 1 is 50 mg, 55 mg, 60mg, 75mg, 80mg, or 90 mg calculated by free base. In some embodiments, the individual has a low AS and the low dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg calculated by free base. In some embodiments, the individual has a low AS and the low dose of Compound 1 is 50 mg, 55 mg, 60mg, 75mg, 80mg, 90 mg, or 100 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the maximum tolerated dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the high dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the maximum tolerated dose of Compound 1 is 200 mg, 220 mg, 240 mg, 250 mg, 300 mg, 320 mg, 350 mg, or 360 mg calculated by free base. In some embodiments, the individual has a high AS from 1.5±0.25 to 2.25 and the high dose of Compound 1 is 200 mg, 220 mg, 240 mg, 250 mg, 300 mg, 320 mg, 350 mg, or 360 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the one-half maximum tolerated dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the intermediate dose of Compound 1 is about 125 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, or about 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the one-half maximum tolerated dose of Compound 1 is 100 mg, 110 mg, 120 mg, 125mg, 150 mg, 160 mg, 175 mg, or 180 mg calculated by free base. In some embodiments, the individual has an intermediate AS from 0.75±0.25 to 1.25±0.25 and the intermediate dose of Compound 1 is 125mg, 150 mg, 160 mg, 170 mg, 175 mg, or 180 mg calculated by free base. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25 and the one-quarter maximum tolerated dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, or about 90 mg calculated by free base. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25 and the low dose of Compound 1 is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg calculated by free base. In some embodiments, the individualWSGR Docket No. 55776-729.601 has a low AS from 0.25 to 0.5±0.25 and the one-quarter maximum tolerated dose of Compound 1 is 50 mg, 55 mg, 60mg, 75mg, 80mg, or 90 mg calculated by free base. In some embodiments, the individual has a low AS from 0.25 to 0.5±0.25 and the low dose of Compound 1 is 50 mg, 55 mg, 60mg, 75mg, 80mg, 90 mg, or 100 mg calculated by free base. In some embodiments, the individual has a high AS and is administered about 200 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 220 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 240 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 240 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 250 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 300 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 300 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 350 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered about 360 mg of Compound 1 calculated by free base. In some embodiments, the individual has a high AS and is administered 360 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 120 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered 120 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 160 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 175 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered 175 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered about 180 mg of Compound 1 calculated by free base. In some embodiments, the individual has an intermediate AS and is administered 180 mg of Compound 1 calculated by free base. In some embodiments, theWSGR Docket No. 55776-729.601 individual has a low AS and is administered about 50 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 60 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered 60 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 75 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered 75 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 80 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 90 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered 90 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has a low AS and is administered 100 mg of Compound 1 calculated by free base.

[0043] In some embodiments, the individual has an AS of 0.25 and is administered a dose of about 100 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to 0.75 and is administered a dose of about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to 1.25 and is administered a dose of about 150 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 0.5 to 1.25 and is administered a dose of about 170 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 1.0 to 2.25 and is administered a dose of about 250 mg of Compound 1 calculated by free base. In some embodiments, the individual has an AS of 1.5 to 2.25 and is administered a dose of about 250 mg of Compound 1 calculated by free base.Certain Terminology

[0044] Unless otherwise stated, the following terms used in this application have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. The use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0045] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, z.e., the limitations of the measurement system. For example,WSGR Docket No. 55776-729.601“about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.

[0046] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0047] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0048] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity. In some embodiments, modulation is an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5HT2A) are modulators of the receptor.

[0049] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function of the receptor.

[0050] The term “agonism,” as used herein, generally refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0051] The term “agonist,” as used herein, generally refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, a “5HT2A agonist” can be used to refer to a compound that exhibits an EC50 with respect to 5HT2A activity of no more than about 100 pM. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates aWSGR Docket No. 55776-729.601 receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

[0052] The term “positive allosteric modulator,” as used herein, generally refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0053] The term “antagonism,” as used herein, generally refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and blocks function of the receptor.

[0054] The term “antagonist” or “neutral antagonist,” as used herein, generally refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist may have no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

[0055] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0056] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0057] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.WSGR Docket No. 55776-729.601

[0058] The term “subject,” “individual,” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[0059] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0060] The term “pharmaceutically acceptable,” as used herein, generally refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0061] The term “pharmaceutically acceptable salt,” as used herein, generally refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley - VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Ztirich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the saltforming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.Neuropsychiatric Disease and Disorders

[0062] Neuronal plasticity has been attributed to many neurological diseases and disorders. For example, during development and in adulthood, changes in dendritic spine number and morphologyWSGR Docket No. 55776-729.601(e.g., lengths, crossings, density) accompany synapse formation, maintenance, and elimination; these changes are thought to establish and remodel connectivity within neuronal circuits. Furthermore, dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, whereas long-term depression is associated with spine shrinkage.

[0063] In addition, dendritic spines undergo experience-dependent morphological changes in live animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and patterns of connectivity in neuronal circuits. For example, disease-specific disruptions in dendritic spine shape, size, and / or number accompany neurological diseases and disorders, such as, for example, neurodegenerative (e.g., Alzheimer’s disease or Parkinson’s disease) and neuropsychiatric (e.g., depression or schizophrenia) diseases and disorders, suggesting that dendritic spines may serve as a common substrate in diseases that involve deficits in information processing.

[0064] In some embodiments, disclosed herein are methods of treating a neuropsychiatric disease or disorder with Compound 1. In some embodiments, provided herein is a method of treating a mood disorder with Compound 1. In some embodiments, provided herein is a method of treating depression (e.g., clinical depression, persistent depressive disorder, bipolar disorder, postpartum depression, suicidal ideation, major depressive disorder, seasonal depression, treatment resistant depression, and the like) with Compound 1. In some embodiments, the depression is major depressive disorder.

[0065] In some embodiments, Compound 1 improves dendritic spine number and dendritic spine morphology that is lost in neurological diseases and disorders.5-HT2A

[0066] 5 -HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). In some embodiments, 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, e.g., DMT, LSD, and DOI. Furthermore, DMT and other psychedelic compounds promote increased dendritic arbor complexity, dendritic spine density, and synaptogenesis through a 5-HT2A-dependent process.

[0067] Compound l is a non-hallucinogenic compound that demonstrate similar or improved therapeutic potential as hallucinogenic 5-HT2A agonists. In some embodiments, Compound 1 provides better therapeutic potential than hallucinogenic 5-HT2A agonists for neurological or neuropsychiatric diseases or disorders. In some embodiments, Compound l is a 5-HT2A modulator and promotes neural plasticity (e.g., cortical structural plasticity and neurite outgrowth). In some embodiments, Compound 1 promotes neural plasticity. In some embodiments, provided herein is aWSGR Docket No. 55776-729.601 method of treating a neuropsychiatric disease or disorder characterized by decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof. In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.

[0068] In some embodiments, Compound 1 is a 5-HT2A agonist. In some embodiments, Compound 1 is a 5-HT2A agonist and promotes neural plasticity (e.g., cortical structural plasticity), such as increases neurite outgrowth. In some embodiments, Compound 1 provides (significant) 5- HT2Aagonism and promotes neural plasticity (e.g., cortical structural plasticity), such as increases neurite outgrowth. In some embodiments, Compound 1 promotes neural plasticity (e.g., cortical structural plasticity), and has a low potential for hallucinogenic activity (e.g., is non- hallucinogenic). In some embodiments, Compound 1 does not elicit dissociative side-effects.

[0069] In some embodiments, Compound 1 is used to treat neurological diseases. In some embodiments, the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.

[0070] In some embodiments, Compound 1 is used for increasing neuronal plasticity. In some embodiments, Compound 1 is used for treating a brain disorder. In some embodiments, Compound 1 is used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.

[0071] Non-limiting examples of experiments or assays to demonstrate the increased neuronal plasticity of Compound 1 include: a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments).WSGR Docket No. 55776-729.601Compound 1

[0072] Disclosed herein is Compound 1 having the structuremethoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, maleate salt). Individual stereoisomers are obtained by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, Compound 1 is prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of Compound 1. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0073] In further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0074] In some embodiments, a metabolite of Compound l is a derivative that is formed when the compound is metabolized. In some embodiments, an “active metabolite” of Compound l is a biologically active derivative of the compound that is formed when the compound is metabolized. In some embodiments, metabolism is the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. In some embodiments, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucanosyltransferases catalyze the transfer of an activated glucuronic -acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. In some embodiments, a metabolite of Compound 1 is optionally identified either by administration of compounds to a host and analysis of tissue samplesWSGR Docket No. 55776-729.601 from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0075] In one aspect, disclosed herein is a method of treating a neuropsychiatric disease or disorder in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a metabolite of Compound 1. In some embodiments, theWSGR Docket No. 55776-729.601Synthesis of Compounds

[0076] Compound 1 was synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein, for example those published in US Patent Application Number 17 / 570,997 which is hereby incorporated by reference for such disclosure. For example, a solution of (R)-l-(5-m ethoxy- IH-indol-l -yl)-N,N-dimethylpropan-2- amine is cooled in an ice bath and a solution of maleic acid is added dropwise while stirring. The ice bath may be removed and the reaction allowed to stir at room temperature. The mixture is then concentrated and triturated to yield Compound 1.

[0077] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0078] Compound 1 was prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc.Pharmaceutical compositions

[0079] In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0080] In some embodiments, Compound 1 is formulated into a pharmaceutical composition. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds.,WSGR Docket No. 55776-729.601Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0081] In some embodiments, Compound 1 is administered either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition. Administration of Compound 1 can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon the condition and disorder of the recipient.

[0082] In some embodiments, Compound 1, is formulated for oral administration. In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0083] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The pharmaceutical composition may be a capsule comprising a capsule shell, such as a hydroxypropyl methylcellulose (HPMC, Hypromellose) capsule shell. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspendedWSGR Docket No. 55776-729.601 in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0084] In some embodiments, provided herein is a pharmaceutical composition comprising Compound 1. In some embodiments, provided herein is a pharmaceutical composition comprising an effective amount of Compound 1. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is a capsule or a tablet. In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 1 mg to 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 2 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 6 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 30 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 30 mg to about 100 mg of Compound 1 calculated by free base. In some embodiments the pharmaceutical composition comprises about 50 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 60 mg to about 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 60 mg to 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 60 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 75 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 75 mg of Compound 1 calculated by free base. In someWSGR Docket No. 55776-729.601 embodiments, the pharmaceutical composition comprises about 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 90 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 250 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 240 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 120 mg to about 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 120 mg to 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 120 of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 120 of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 150 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 150 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 180 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 250 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg to about 500 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg to about 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 240 mg to 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 250 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 240 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 240 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 300 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises about 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition comprises 360 mg of Compound 1 calculated by free base. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient. In some embodiments, theWSGR Docket No. 55776-729.601 pharmaceutical composition is a tablet or capsule further comprising hypromellose and / or titanium dioxide. In some embodiments, the pharmaceutical composition is a capsule further comprising hypromellose and titanium dioxide. In some embodiments, multiple pharmaceutical compositions are administered in combination to achieve a target dose. For example, one pharmaceutical compositions comprising 50mg of Compound 1 calculated by free base and three pharmaceutical compositions comprising lOmg of Compound 1 calculated by free base may be combined to equal a total administered dose of 80 mg of Compound 1 calculated by free base.

[0085] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Methods of Treatment, Dosing and Treatment Regimens

[0086] Compound 1 is useful for promoting neuronal growth and / or improving neuronal structure.

[0087] Compound l is a non-hallucinogenic psychoplastogens that useful for treating one or more diseases or disorders associated with loss of synaptic connectivity and / or plasticity.

[0088] In some embodiments, provided herein is a method of promoting neural plasticity (e.g., cortical structural plasticity) in an individual by administering Compound 1 to the individual. In some embodiments, provided herein are methods of modulating 5-HT2A in an individual by administering Compound 1 to the individual. In some embodiments, provided herein are methods of agonizing 5-HT2A in an individual by administering Compound 1 to the individual. In some embodiments, the individual has or is diagnosed with a brain disorder or other conditions described herein.

[0089] In some embodiments, provided herein is a method of promoting neuronal growth in an individual in need thereof, comprising administering to the individual in need thereof Compound 1.

[0090] In some embodiments, provided herein is a method of improving neuronal structure in an individual in need thereof, comprising administering to the individual in need thereof Compound 1.

[0091] In some embodiments, provided herein is a method of modulating the activity of 5- hydroxytryptamine receptor 2A (5-HT2A) receptor in an individual in need thereof, comprising administering to the individual in need thereof Compound 1.

[0092] In some embodiments, provided herein is a method of treating a disease or disorder in an individual in need thereof that is mediated by the action of 5 -hydroxytryptamine (5-HT) at 5- hydroxytryptamine receptor 2A (5-HT2A), comprising administering to the individual in need thereof Compound 1.WSGR Docket No. 55776-729.601

[0093] In some embodiments, provided herein is a method of treating a disease or disorder in an individual in need thereof that is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering to the individual in need thereof Compound 1.

[0094] In some embodiments, provided herein is a method of treating a neurological disease or disorder in an individual in need thereof, comprising administering to the individual in need thereof Compound 1.

[0095] In some embodiments, an individual administered Compound 1 does not have a hallucinogenic event. In some embodiments, administering Compound 1 to the individual does not cause hallucinations, dissociative effects, or psychomimetic effects. In some embodiments, Compound 1 is non-hallucinogenic, non-dissociative, and non-psychomimetic. In some embodiments, administering Compound 1 to the individual does not cause hallucinations, dissociative effects, or psychomimetic effects as determined by a Clinician-Administered Dissociative States Scale (CDSS), a Bond-Lader Visual Analog Scale (VAS), a Bowdle VAS, or a Revised Mystical Experience Questionnaire (MEQ-30), or a combination thereof. In some embodiments, the CADSS value is less than 5, or is less than 3, or is less than 2, or is less than 1. In some embodiments, the CADSS value is less than 5, or is less than 3, or is less than 2, or is less than 1 at any point after administering Compound 1. In some embodiments, the Bond-Lader VAS value is between 25-75, or is between 30-70, or is between 35-65 for each measure on the scale. In some embodiments, the Bond-Lader VAS value is between 25-75, or is between 30-70, or is between 35-65 for each measure on the scale at any point after administering Compound 1.

[0096] In some embodiments, described herein are methods for treating a disease or disorder, wherein the disease or disorder is a neurological diseases and disorder.

[0097] In some embodiments, Compound 1 is used to treat neurological diseases. In some embodiments, Compound 1 has, for example, anti -addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.

[0098] In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post -traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is aWSGR Docket No. 55776-729.601 psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post -traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia. In some embodiments, the neuropsychiatric disease is depression, addiction, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the neuropsychiatric disease is depression. In some embodiments, the depression is treatment resistant depression, major depressive disorder, suicidal ideation, or combinations thereof. In some embodiments, the depression is major depressive disorder.

[0099] In some embodiments, Compound 1 is useful for the modulation of a 5- hydroxytryptamine (5-HT) receptor. In some embodiments, the 5-HT receptor modulated by Compound 1 is 5-hydroxytryptamine receptor 2A (5-HT2A).

[0100] In some embodiments, Compound 1 is used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of 5-HT2A activity.

[0101] In some embodiments, Compound 1 is used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from promoting neuronal growth and / or improving neuronal structure.

[0102] In one embodiment, Compound 1 is administered to the individual orally. In some embodiments, Compound 1 is administered to the individual at a dose of about 1 mg to about 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 1 mg to about 10 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 2 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 6 mg calculated byWSGR Docket No. 55776-729.601 free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 10 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual a dose of about 10 mg to about 30 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 20 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 30 mg to about 100 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 50 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 60 mg to about 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 60 mg to 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 60 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 60 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 75 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 75 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 80 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 90 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 100 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 100 mg to about 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 120 mg to about 180 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 120 mg to 180 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 120 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 120 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 150 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 150 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 160 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 170 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 170 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 180 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 180 mg calculatedWSGR Docket No. 55776-729.601 by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 200 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 220 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg to about 500 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 250 mg to about 500 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg to about 360 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 240 mg to 360 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 240 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 240 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 250 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 300 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 300 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 350 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of about 360 mg calculated by free base. In some embodiments, Compound 1 is administered to the individual at a dose of 360 mg calculated by free base.

[0103] In some embodiments, the individual in need thereof is fasted prior to administering Compound 1. In some embodiments, the individual in need thereof is sated prior to administering Compound 1. In some embodiments, the individual in need thereof is fasted or sated prior to administering Compound 1.

[0104] In some embodiments, Compound 1 is administered once per day. In some embodiments, Compound 1 is administered once every 2 days. In some embodiments, Compound 1 is administered once every 3 days. In some embodiments, Compound 1 is administered 3 times a week. In some embodiments, Compound 1 is administered 3 times in a 7-day period, wherein there is at least 1 day between each administration. In some embodiments, Compound 1 is administered for at least 3 days, or for at least 5 days, or for at least 7 days, or for at least 10 days, or for at least 14 days, or for at least 21 days, or for at least 28 days. In some embodiments, Compound 1 is administered once every 7 days. In some embodiments, Compound 1 does not accumulate in the individual. In some embodiments, Compound 1 is present in the individual in an amount lower thanWSGR Docket No. 55776-729.601 about Ing / mL after 30 hours administering Compound 1. In some embodiments, Compound 1 is administered in an outpatient setting.

[0105] In some embodiments, Compound 1 achieves a Cmax under about 10 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a Cmax under about 5 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a Cmax at about 2 hours after administering the compound to the individual. In some embodiments, Compound 1 achieves a CSF / Plasma Ratio of about 0.10 to about 0.50, or of about 0.15 to about 0.30, or of about 0.20. In some embodiments, administering Compound 1 produces a sustained therapeutic response for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 days after administration. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 10 ng / mL to about 1,000 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 25 ng / mL to about 500 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 50 ng / mL to about 250 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 75 ng / mL to about 125 ng / mL in the individual. In some embodiments, Compound 1 is administered to an individual in amount such that Compound 1 achieves a Cmax of about 100 ng / mL in the individual.

[0106] In some embodiments, administering Compound 1 to the individual does not cause cardiotoxicity. In some embodiments, Compound 1 is not cardiotoxic. In some embodiments, Compound 1 does not activate the 5-HT2B receptor. In some embodiments, a risk of the individual developing any serious treatment-emergent adverse event (TEAE) is less than about 60%, or less than about 50%, or less than about 40%, or less than about 30%, or less than about 20%, or less than about 10%, or less than about 5%.

[0107] In some embodiments, administering Compound 1 to an individual increases neurite differentiation, neurite length, spinogenesis, or a combination thereof in the individual. In some embodiments, the increase is greater than 1.0-fold. In some embodiments, administering Compound 1 increases frequency and amplitude of layer V pyramidal neurons 24 hours after administration.

[0108] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the individual multiple times over the span of one day. In some embodiments, administering Compound 1WSGR Docket No. 55776-729.601 produces a therapeutic effect within about 48 hours, or within about 24 hours. In some embodiments, the therapeutic effect is an anti-depressive effect. In some embodiments, the individual experiences a therapeutic effect after a single administration of Compound 1.

[0109] In some embodiments, an individual administered Compound 1 has a diagnosis of major depressive disorder (MDD) that has been present for 12-week to 2 years and / or has a Hamilton Rating Scale for Depression, 17-item (HAM-D) total score of at least 14, such as at least 22, prior to administering Compound 1. In some embodiments, an individual administered Compound 1 has a diagnosis of major depressive disorder (MDD) that has been present for 12-week to 2 years. In some embodiments, an individual administered Compound 1 has a Hamilton Rating Scale for Depression, 17-item (HAM-D) total score of at least 14, such as at least 22, prior to administering Compound 1.

[0110] In some embodiments, an individual administered Compound 1 does not have: a) a cytochrome P450 2D6 (CYP2D6) activity score (AS) of less than 0.25 or greater than 2.25, b) psychosis or a history of psychosis, c) seizures or a history of seizures, d) bipolar disorder, schizophrenia, and / or schizoaffective disorder or a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder, e) a history of alcohol or drug dependence or use of psychedelics within the 12 months prior to administering Compound 1, or f) any combination of a) through e). In some embodiments, an individual administered Compound 1 does not have a cytochrome P450 2D6 (CYP2D6) activity score (AS) of less than 0.25 or greater than 2.25. In some embodiments, an individual administered Compound 1 does not have psychosis or a history of psychosis. In some embodiments, an individual administered Compound 1 does not have seizures or a history of seizures. In some embodiments, an individual administered Compound 1 does not have bipolar disorder, schizophrenia, and / or schizoaffective disorder or a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder. In some embodiments, an individual administered Compound 1 does not have a history of alcohol or drug dependence or use of psychedelics within the 12 months prior to administering Compound 1. In some embodiments, an individual administered Compound 1 has not received therapy with a strong inhibitor and / or inducer of cytochrome P450 (CYP)2D6 within 14 days or 5 half-lives (whichever is longer) prior to administering Compound 1. In some embodiments, Compound 1 is administered without a strong CYP2D6 inhibitor or inducer.

[0111] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of theWSGR Docket No. 55776-729.601 subject). Thus, in some embodiments, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.EXAMPLES

[0112] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Example 1: Preclinical Pharmacology of Compound 1 that is a Novel Non-Hallucinogenic Neuroplastogen for Treating Neuropsychiatric Diseases

[0113] This example illustrates the preclinical pharmacology of Compound 1 disclosed herein.

[0114] Background

[0115] Cortical synaptic atrophy is a critical component of many neuropsychiatric disorders and treatments that promote structural neuroplasticity, in key brain areas, show efficacy in treating them. Psychedelic agents, including the dissociative anesthetic ketamine and the serotonergic psilocybin, have been reported to show efficacy in humans for treating multiple neuropsychiatric disorders. The clinical effects of these compounds are hypothesized to be due to their ability to promote rapid and enduring effects on structural neuroplasticity in key brain areas, and as such, these compounds have been classified as psychoplastogens. The dissociative experiences, hallucinations, and / or cardiotoxic properties of these compounds will limit their widespread clinical use. Bringing these transformative therapies to a greater patient population will require an orally bioavailable, non-hallucinogenic compound that maintains the rapid and enduring effects of psychoplastogens, or a “neuroplastogen.” To that end, isotryptamine Compound 1 was developed as a potent, orally active neuroplastogen, promoting rapid and enduring behavioral efficacy and structural plasticity without pro-hallucinogenic activity or cardiotoxicity.

[0116] Results(a) Compound 1 is an orally active, brain penetrant, small molecule.(b) Compound 1 has a unique poly-pharmacological profile in traditional in vitro RLB binding / functional assays.(c) Compound 1 promotes structural plasticity in vitro.(d) Compound 1 is active in multiple behavioral models of antidepressant activity.(e) Compound 1 promotes structural and functional neuroplasticity in PFC layer V pyramidal neurons at the same doses that are active in behavioral assays.(f) Compound 1 does not have hallucinogenic properties.(g) Compound 1 is predicted to have rapid and enduring anti-depressant effects in humans without producing hallucinations.WSGR Docket No. 55776-729.601(h) In a phenotypic screen of neurite outgrowth in neuronal cell cultures, Compound 1 produced significant increases in both neurite length and complexity.(i) In vivo, Compound 1 demonstrated significant effects on promoting both structural and functional neuroplasticity on par with the 1stgeneration compounds after a single dose.(j) Compound 1 in vivo behavioral data exhibited both rapid, within 24-hours, and enduring, up to 7 days, antidepressant-like activity after a single dose.(k) In studies relevant to cardiotoxicity and hallucinations, no signal was identified for Compound 1.(l) Importantly, Compound 1 met or exceeded the efficacy and endurance of first- generation psychoplastogens, including DMT, psilocybin, and ketamine.

[0117] FIG. 1 illustrates that Compound 1 promotes structural plasticity in vitro. Compound 1 treatment increases neuronal differentiation in vitro. Isolated rat cortical neurons treated for 72 hrs (FIG. 1A) in culture showed an increase in neurite differentiation (FIG. IB) compared to control. Changes in neurite length upon Compound 1 treatment showed an increase in a concentration dependent manner I. (**p < 0.01, ***p < 0.001 using one-way ANOVA followed by post-hoc Fisher’s LSD)

[0118] FIG. 2A-2E illustrate that Compound 1 produced rapid and enduring antidepressant-like effects. Compound 1 produced rapid and enduring antidepressant-like activity in a rat model of depression. FIG. 2A illustrates that the rat forced swim test revealed rapid antidepressant -like activity after a single IP injection 24 hours before testing. FIG. 2B illustrates that antidepressantlike effects were durable and remained observable 7-days post administration. FIG. 2C illustrates that antidepressant-like effects were observed 24 hours after oral administration. *p<0.05 one-way ANOVA. Dunnett’s post-hoc test.

[0119] Compound 1 produced rapid antidepressant-like activity in two mouse models of depression. FIG. 2D illustrates that the mouse tail suspension test showed antidepressant -like activity 30 minutes after treatment. FIG. 2E illustrates Compound 1 reversed a stress-induced social deficit in mouse chronic social defeat. C57BL / 6 mice exposed to aggressors for 10 days were assessed for social preference of a novel conspecific. Stress susceptible mice (left bars) and were administered vehicle, ketamine, psilocybin, or Compound 1 and assessed a second time for their social preference (right bars). *p<0.05 one-way ANOVA. Dunnett’s post-hoc test for A-D. *p<0.05 two-model ANOVA Sidak’s multiple comparison test (pre vs post dose) for E.

[0120] FIG. 3 illustrates that Compound 1 achieves high plasma and brain levels following oral administration in multiple species. Compound 1 has a unique poly-pharmacological profile. At exposures relevant for neuroplasticity and behavioral efficacy, Compound 1 appears to bind anWSGR Docket No. 55776-729.601 array of targets relevant to neuropsychiatric disorders. In traditional radioligand binding / functional assays, Compound 1 was found to engage 5-HT2C, 5-HT1D, 5-HT3, Sigma-1 receptors, and MAO-A. Importantly, antagonist experiments indicate that 5HT2A / 2C receptors play an important role in the proplastic effects of Compound 1 and it does not activate 5HT2B.

[0121] FIG. 4A and 4B illustrate that Compound 1 does not produce head twitches in rodents. Compound 1 did not produce a significant number of head twitches when administered to mice at high doses (10 or 30mg / kg, IP) (FIG. 4A). Similarly, therapeutic and supratherapeutic doses of Compound 1 did not produce a significant number of head shakes in rats (FIG. 4B).

[0122] FIG. 5A-5F illustrate that Compound 1 promotes structural plasticity in the PFC in vivo at behaviorally relevant doses. FIG. 5A illustrates in vivo dendritic spinogenesis assay. FIG. 5B illustrates Golgi stained layer V PFC pyramidal neurons. FIGs. 5C-5D illustrate Compound 1 - induced spinogenesis in vivo. FIGs. 5E-5F illustrate psilocybin and ketamine induced spinogenesis in vivo. Compound 1, at behaviorally relevant and efficacious doses, increased dendritic spine density in layer-V PFC pyramidal neurons of rat brain 24 hours following a single dose (FIG. 5A) as shown by Golgi -impregnated neurons (FIG. 5B). Compound 1 treatment induced changes are quantified as spine density (# of spines / dendritic length)(FIGs. 5C-5D). Changes in Compound 1 induced spine density are similar to ketamine and psilocybin (FIGs. 5E-5F). *p<0.05, ** p<0.01 using two-way ANOVA followed by Tukey’s post-hoc test.

[0123] FIG. 6A-6F illustrate that Compound 1 increases functional plasticity in the PFC in vivo at behaviorally relevant doses. FIG. 6A illustrates ex vivo functional plasticity assay. FIG. 6B illustrates pEPSC traces from layer V PFC pyramidal neurons. FIGs. 6C-6D illustrate that Compound 1 induced functional plasticity ex vivo. FIG. 6E-6F illustrate DMT, psilocybin, and ketamine induced functional plasticity ex vivo. Compound 1 altered excitatory post-synaptic potentials (EPSCs) in mPFC layer V pyramidal neurons 24 hours after a single in vivo administration of a behaviorally relevant dose. FIG. 6B illustrates raw traces from layer V cells following administration of Compound 1 or Vehicle. Compound 1 increased the cumulative mean frequency (FIGs. 6C, 6E) and the peak amplitude (FIGs. 6D, 6F) of EPSCs recorded from mPFC layer-V pyramidal neurons in rat brain slices. The effect of Compound 1 was similar to DMT, ketamine, and psilocybin tested independently at behaviorally relevant doses relative to controls (FIGs. 6C, 6E). In measures of peak amplitude, Compound 1 responses were similar to DMT, but both differed from ketamine and psilocybin (FIGs. 6D, 6F), indicating potential nuances in neuroplastic mechanisms. *p <0.05, Mann-Whitney U-test.

[0124] Citation of References1. Ly et al., 2018, Cell Reports 23, 3170-3182WSGR Docket No. 55776-729.6012. Olson, Journal of Experimental Neuroscience 12, 1-4Example 2: Use of Compound 1 for Treatment of Major Depressive Disorder (MDD)

[0125] This example illustrates a Phase I study to evaluate the safety, tolerability, and pharmacokinetic profile of neuroplastogen Compound 1 disclosed herein.

[0126] Background

[0127] Psychedelic compounds have demonstrated preliminary efficacy across a range of neuropsychiatric conditions, with effects that are believed to be mediated by their rapid and enduring impact on brain structural neuroplasticity. However, the dissociative experiences and hallucinations produced by these compounds will likely limit their widespread clinical use.

[0128] In an attempt to discover and develop a non- hallucinogenic, non-dissociative plastogenic compound that could be used to treat neuropsychiatric conditions with high unmet need, we synthesized Compound 1, and are examining its safety, tolerability, and pharmacokinetic (PK) profiles in a combined single- and multiple-ascending dose study in healthy volunteers. Compound l is a non-hallucinogenic and non-dissociative isotryptamine neuroplastogen currently undergoing initial human testing to treat those diagnosed with major depressive disorder (MDD) and other associated neuropsychiatric conditions. Preclinical data suggested that in efficacious doses, Compound 1 increased dendritic spine density in rat brain layer-V PFC pyramidal neurons and rapid and enduring antidepressant-like effects after a single dose. Recent Phase 1 data found Compound 1 to be safe and well tolerated in recently reported research, with no serious adverse events reported. In addition, researchers did not observe significant abnormalities among crucial safety indicators, including vital signs, electrocardiogram (ECG) readings, and laboratory analysis.

[0129] Neuroplastogens are a novel class of potentially disease-modifying therapeutics for psychiatric and neurological conditions. These compounds promote rapid and sustained neuroplasticity in selective neural circuits resulting in fast-acting therapeutic effects.Neuroplastogens are chemical entities inspired by compounds that are proving to be beneficial across a range of therapeutic areas including mood, anxiety, cognitive, and neurodegenerative disorders in addition to other synaptopathies with differentiated profiles.

[0130] Methods

[0131] This 3-part inpatient study was being conducted in 106 healthy cytochrome P450 (CYP450) 2D6 genotyped male and female healthy volunteers (HVs) aged 18 to 55. Part A is a randomized, double-blind, placebo- controlled single ascending dose (SAD) study to investigate the safety, tolerability, and PK of single- ascending oral doses of Compound 1 (8 cohorts of 8 participants per cohort each allocated 6:2 to Compound lor placebo, in escalating doses from 2 to 360 mg). Part B is a standard, open-label, two-way crossover design study to investigate the effectWSGR Docket No. 55776-729.601 of food on the PK of Compound 1. In Part B, 10 HVs received a single oral dose of 60 mg of Compound 1 on 2 separate occasions, one in a fed state and the other in a fasted state. The 2 treatments (fasted and fed) are separated by a 7-day washout period. Part C is a randomized, double-blind, placebo- controlled multiple ascending dose (MAD) study in which participants (4 cohorts of 8 participants per cohort each allocated 6:2 to Compound 1 or placebo, in escalating doses from 50 to 350 mg daily for 7 days) received multiple oral doses of either Compound 1 or placebo once a day for up to 7 days. Safety monitoring included clinical and laboratory assessments, serial 12-lead ECGs, vital signs, and emergence of suicidality (Columbia Suicide Severity Rating Scale - C-SSRS) or psychotic symptoms (Brief Psychiatric Rating Scale - BPRS). Pharmacodynamic assessments included clinical measures of psychedelic and psychotomimetic effects (Mystical Experience Questionnaire 30 - MEQ-30, Clinician-Administered Dissociative States Scale - CADSS), neuroendocrine effects, and serial quantitative resting state EEG. Noncompartmental PK analysis of plasma Compound 1 was performed up to 30h post-dose in the SAD and on Days 1 and 7 in the MAD. PK analysis of CSF concentrations of Compound 1 was performed in selected cohorts.

[0132] Brief Summary of Results(a) Compound 1 has been safe and well -tolerated in 106 healthy volunteers dosed to date.(b) No serious adverse events have been reported.(c) No clinically significant abnormalities in laboratory tests, vital signs, ECGs, or other safety measures (e.g., C-SSRS, EEG) have been observed.(d) All Treatment emergent adverse events (TEAE) have been mild in severity, and none have resulted in study drug discontinuation or withdrawal from the study.(e) The most common TEAEs to date include mild dizziness (n=8), mild headache (n=10), and mild nausea (n=10). These were dose-related, time-limited, and resolved without intervention.(f) No psychomimetic, hallucinatory, or dissociative effects have been observed, as reflected by no change over time on a robust battery of measures, including Clinician-Administered Dissociative States Scale (CADSS), Bond-Lader Visual Analogue Scales (VAS) (Mood Rating Scale) (B&L VAS), Bowdle VAS, and Mystical Experience Questionnaire (MEQ-30).(g) Data demonstrate that Compound 1 is orally bioavailable, achieves plasma exposures within the predicted therapeutic range, and achieves measurable levels within the Cerebrospinal fluid (CSF).(h) Pharmacokinetics demonstrate dose-proportionality across cohorts, limited food effect, and no accumulation over 7 days of administration.WSGR Docket No. 55776-729.601(i) While plasma PK demonstrated dose-proportionality in SAD Cohorts 1 through 5 and MAD Cohorts 1 and 2, a strong CYP2D6 phenotype-dependent effect on plasma concentrations and higher-than-expected intersubject PK variability were observed (FIGs. 17A and 17B). Subjects with similar CYP2D6-based gene activity scores (AS) were included in subsequent cohorts: in SAD Cohort 6 (160 mg) and MAD Cohort 3 (120 mg) subjects with CYP2D6 AS of 1.0-1.5 (intermediate / normal CYP2D6 activity), and in SAD Cohorts 7 (220 mg) and 8 (360 mg), and MAD Cohort 4 (350 mg) subjects with CYP2D6 AS of 2.0 (high CYP2D6 activity) were included, respectively, after which intersubject PK variability decreased adequately (FIGs.18A, 18B)(j) PK curves for subjects administered Compound 1 and having 0.25, 0.5, 1.0, 1.25, and 2.0 CYP2D6-based gene activity scores (AS) were dose-normalized and demonstrate adequate intersubject variability (FIG. 19).

[0133] Patient characteristics, including CYP2D6 activity score, are summarized in Table 1 below.Table 1WSGR Docket No. 55776-729.601

[0134] Conclusions(a) Data from the ongoing Phase I study support the continued clinical development of Compound 1.(b) Clear demonstration of Compound l’s lack of psychomimetic, hallucinatory, or dissociative effects - in keeping with results from pre-clinical studies - provides “proof of platform” for growing library of non-hallucinogenic neuroplastogens.(c) Promotion of neuroplasticity plays a critical role in the efficacy and time to onset of antidepressant activity across different modalities (SSRIs, ketamine, ECT), and, as described herein, preclinical data demonstrated that Compound 1 produces rapid and durable increases in structural and functional neuroplasticity in prefrontal cortex (PFC) layer V pyramidal neurons.(d) Measurable CSF drug concentrations and observed increases in low frequency EEG bands coinciding with neuroendocrine effects support the conclusion that Compound 1 reaches the CNS and demonstrates central target engagement with no dissociative, hallucinatory or psychotomimetic effects.(e) The observed qEEG pattern is similar to the signature of slow-wave power increases induced by ECT in depressed patients (Hill et al 2020) as well as the pattern observed after ketamine (Curie et al 2021) and 5-MeO-DMT (Blackburne et a 2024) exposure. Accordingly, slow- wave power serves as a translational marker of cortical plasticity and synaptic strength.(f) Given its emerging clinical and preclinical profile, Compound 1 has the potential to address significant unmet needs within MDD and related neuropsychiatric disorders as a novel, fastacting, outpatient oral pharmacotherapy.

[0135] Results

[0136] FIG. 7 illustrates the study schematic of the human clinical trial.

[0137] FIG. 8 illustrates the sample characteristics of subjects enrolled in the clinical trial.

[0138] FIG. 9 illustrates the TEAEs by preferred term of subjects enrolled in the clinical trial.

[0139] FIGs. 10A and 10B illustrate CADSS total score over time in subjects of the SAD cohort (FIG. 10A) and MAD cohort (FIG. 10B) respectively.

[0140] FIGs. 11A-11C illustrate bond and lader (B&L) visual analogue scale mean value over time in subjects of the SAD cohort (FIG. 11 A) and MAD cohort (FIG. 11B) respectively. FIG. 5C illustrates the B&L visual analogue scale.

[0141] FIGs. 14A-14D illustrate summary pharmacokinetics of Compound 1 in plasma of subjects of the SAD, Food Effect and MAD cohorts.

[0142] FIG. 15 illustrates the CSF / Plasma ratio of Compound 1.1. Citation of Reference(Bond & Lader 1974)WSGR Docket No. 55776-729.601Example 3: A Phase lb Study to Evaluate the Pharmacodynamics, Safety, and Tolerability of Compound 1 in Participants with Major Depressive Disorder

[0143] This is a Phase lb, dose-blinded, single-center study in untreated participants with recurrent MDD and defined cytochrome P450 CYP2D6 activity scores (AS). Participants are assigned to a dose level based on CYP2D6 AS to obtain comparable Compound 1 exposures across all participants. Participants receive oral doses of Compound 1 according to the following scheme:• Cohort A: A dosing regimen of once daily doses on Days 1 through 7; or• Cohort B: An intermittent dosing regimen of a single dose on Day 1 and Day 4.

[0144] Dosing was conducted under fed conditions on each dosing day. The Compound 1 dose for each participant depended on the CYP2D6 AS (determined from a blood sample taken during the screening period), with participants being classified as:• ASlow = 0.25,• ASintermediate = 0.5-1.25, or• AShigh = 1.5-2.25.Participants in the ASlow group received a dose of 100 mg. Participants in the ASintermediate group received a dose of 170 mg. Participants in the AShigh group received a dose of 250 mg. Each participant was administered 5 capsules on a dosing day as a combination of active and placebo capsules, such that the Compound 1 dose received was blinded to the participant, study staff, and assessors. The study included a screening period of up to 42 days, a 10-day inpatient treatment period (including 2 days of baseline assessments, up to 7 days of daily treatment, and posttreatment follow-up) and a 4-week outpatient follow-up period. Beginning on Day -2, eligible participants were admitted to the inpatient unit to complete baseline assessments. On Day 1 through Day 7, (once daily dosing scheme, Cohort A) or on Days 1 and 4 (intermittent dosing scheme, Cohort B), participants receive an oral dose of Compound 1 in line with the assigned dosing regimen. The dose levels selected for this study are based on safety, tolerability and PK / pharmacodynamic (PD) data in healthy participants in the first-in-human (FIH) study, and in consideration of nonclinical pharmacology and toxicology data. Compound 1 has been administered to healthy participants up to 360 mg as a single dose and up to 350 mg as a once daily dose for 7 days. Compound 1 PK is impacted by CYP2D6 activity; as a result, participants are assigned to one of 3 AS categories (low, intermediate, or high) and receive a once daily dose or an intermittent dose of Compound 1 and dose level will be according to their CYP2D6 AS. The dose levels achieve an exposure range that is comparable across the AS categories. Based onWSGR Docket No. 55776-729.601 repeat-dose PK data from the FIH study, the doses in this study (100 mg for ASlow, 170 mg for ASintermediate and 250 mg for AShigh) are predicted to generate a mean Cmax and AUC of approximately 100 ng / mL and 585 ng»h / mL, respectively, in each AS category.

[0145] An exemplary Compound 1 dosing scheme is provided in Table 2 below, predicted to generate a mean Cmax and AUC of approximately 100 ng / mL and 585 ng»h / mL, respectively, in each AS category.Table 2AS=activity score; AUC=area under the plasma concentration-time curve Cmax=maximum observed plasma concentration; DN=dose-normalized; N=number of participants

[0146] The predicted exposures are within the range of previous clinical experience and substantially below the exposures associated with the no-observed-adverse-effect-level (NOAEL) in a rat 28-day toxicology study (NOAEL 100 mg / kg; Cmax = 1200 ng / mL; AUC 5070 ng»h / mL). Evidence of central nervous system (CNS) activity, as demonstrated by increased absolute power in the theta and delta bands of the EEG, was observed in the FIH study at plasma concentrations of 65 ng / mL, indicating that a concentration of 100 ng / mL also has the potential to elicit pharmacodynamic effects in this study. Thus, the doses in this study are expected to provide sufficient exposures to enable the evaluation of pharmacodynamic effects of Compound 1 in a relevant study population of participants with MDD while remaining within previous human exposures and below toxicology limits. Upon admission to a research unit participants completed habituation and baseline assessments, including polysomnography (PSG), quantitative electroencephalography (qEEG), and clinical symptom scales. Beginning on day 1, participants in Cohort A received Compound 1 once daily for 7 days. On days 1, 4, and 7, qEEG was collected while awake; on the evenings of day 1 and day 7, PSG was collected overnight. Clinical measures were collected daily. After discharge from the unit on day 8, participants returned for assessments on Days 22 and 36.WSGR Docket No. 55776-729.601

[0147] Results: Mean age at admission was 33 years (range 23 to 54), with 5 / 9 (55%) females. Mean HAM-D of 18.8 (SD= 2.4), and mean MADRS of 27.2 (SD=4.2) indicated moderate depression severity at baseline. Co-morbid anxiety measured by the HAM-A was low at baseline (Mean=12.0, SD=4.5). All 9 participants completed the 7-day treatment period. Compound 1 was well-tolerated, with no discontinuations due to adverse events (AEs) and only mild AEs reported. The most frequent Compound 1 -related AEs were nausea (n=5), tiredness (n=4), and headache (n=4). Nausea was tracked using a daily Visual Analogue Scale and was mild, self-limited, and required no intervention. There were no changes in safety parameters, including vital signs, ECGs, laboratory measures, or physical exam findings. Consistent with the previous phase I healthy volunteer study, there was no evidence of psychotomimetic, hallucinatory, or dissociative effects, as measured by the MEQ-30, BPRS, and CADSS. Cognitive performance remained unchanged, as measured by a computerized Symbol Coding task. Plasma levels of Compound 1 were consistent with target exposures.

[0148] The primary endpoint — change from baseline to end of treatment on brain slow-wave activity (SWA) — is an emerging translational measure of cortical plasticity and synaptic strength (Duncan et al. 2013). Cohort A demonstrated a pharmacodynamic signal consistent with that previously observed in the phase I healthy volunteer study - namely, a consistent increase in slow- wave theta activity, with other non-specific qEEG changes also observed. Increases in theta activity were observed using both a traditional wet electrode 64-channel EEG acquisition system (Biotrial, Inc) and novel 16-channel dry EEG headset (Cumulus NeuLogiq platform). From an efficacy perspective, rapid, meaningful, and sustained decreases in depression scores were observed across most participants. By day 8, 8 / 9 (88.9%) participants demonstrated an improvement on the MADRS, with 4 / 9 (44.4%) meeting criteria for MDD response (defined as 50% reduction in MADRS score from baseline). Participants have continued to show improvement on the MADRS up to 4 weeks after completing a 7-day course of Compound 1. MADRS change from baseline at Day 7 for Cohort A was negatively correlated with Compound 1 Cmax measured on Day 1 (FIG. 21). Together, these data suggest that Compound 1 addresses significant unmet needs in patients with MDD and reinforces the concept that promotion of neuroplasticity plays a critical role in the efficacy of Compound 1.Example 4: Phase lb study objectives and endpoints

[0149] Objectives: Primary:• To assess the effects of Compound 1 on translational biomarkers associated with neuroplasticity in participants with recurrent MDD.WSGR Docket No. 55776-729.601

[0150] Objectives: Secondary:• To assess the safety, tolerability, and PK of Compound 1 in participants with recurrent MDD.• To assess the effects of Compound 1 on depression, anxiety, and other psychiatric symptom measures in participants with recurrent MDD.

[0151] Objectives: Exploratory• To assess the effects of Compound 1 on additional translational biomarkers associated with neuroplasticity in participants with recurrent MDD.Example 5: Phase lb study population

[0152] Participant demographics and treatments for Cohort A in the Phase lb study are summarized in Table 3.Table 3'Number of major depressive episodes (MDE), excluding the current episode2Length of current major depressive episode, in months

[0153] Inclusion criteria:• Participant is male or female between 18 and 55 years of age, inclusive.• Participant has a body mass index between 18 kg / m2and 30 kg / m2, inclusive.• Participant is >50 kg.• Participants living with recurrent MDD and otherwise in good physical health and with noWSGR Docket No. 55776-729.601 clinically significant findings, as determined by the Investigator, on physical examination, 12- lead ECG, or clinical laboratory tests.• Participant has a diagnosis of recurrent MDD that has been present for at least a 12-week period (up to a maximum of 2 years) for the current major depressive episode, with at least one previous major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) and verified by a SAFER interview (Sheehan 1994; Desseilles 2013).• Participant has a HAM-D-17 total score of >14 at screening and at baseline.• Patient is not taking psychotropic medications, including antidepressants, at time of screening. o For patients in whom a psychotropic medication has been recently discontinued by their treating provider, at least 4 weeks must elapse between the day of the last dose and Day -2 of the study (or 5 weeks if the medication in question was fluoxetine).• Participant is willing to delay the start of other antidepressants or pharmacotherapy agents, including as-needed agents, during the study.• At screening, females must not be pregnant or lactating. Nonpregnancy will be confirmed for all females by a negative serum pregnancy test at screening and admission.• Female participants of childbearing potential who have a fertile male sexual partner must agree to use an adequate method of contraception from at least 4 weeks prior first administration of the study drug to at least 3 months after the last dose of the study drug.• All prescribed non-psychotropic medication must have been stopped at least 4 weeks prior to admission to the clinical research center. An exception is made for hormonal contraceptives, which may be used by female participants throughout the study.• All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John’s wort) must have been stopped at least 14 days prior to admission to the clinical research center. An exception is made for paracetamol, which is allowed up to admission to the clinical research center (maximum dose allowed: 4 g per day for 5 consecutive days).• Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to screening and admission to the clinical research center.• Ability and willingness to abstain from methylxanthine(e.g. caffeine)-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 48 hours (2 days) prior to admission to the clinical research center.• Participant agrees to adhere to study requirements.

[0154] Exclusion criteria:• History of significant drug and / or food allergies.WSGR Docket No. 55776-729.601• Use of tobacco or nicotine products within 90 days prior to the first drug administration.• Hairstyles which cannot be removed and that may affect the function of qEEG measuring devices used during this study.• Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, gamma hydroxybutyric acid [GHB], tricyclic antidepressants, and alcohol) at screening or admission to the clinical research center.• Average intake of more than 21 units of alcohol per week for men and 14 units of alcohol per week for women (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits).• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or human immunodeficiency virus (HIV) 1 and 2 antibodies.• Participation in a drug or device study within 5 half-lives (as far as known) or less than 30 days prior to the first drug administration in the current study. Participation in 4 or more other drug studies in the 12 months prior to the first drug administration in the current study.• Donation or loss of blood within 60 days prior to the first drug administration.• Significant and / or acute illness within 5 days prior to the first drug administration that may impact safety assessments, in the opinion of the Investigator.• Unsuitable veins for blood sampling.• Participant is a CYP2D6 poor- or ultrarapid-metabolizer, as defined by an AS of 0 or >2.25. Genotyping for CYP2D6 will be obtained during the screening period to exclude poor- and ultrarapi d-metab oli zers .• Participant has a history of suicide attempt in the last 2 years (determined as part of the MINI).• Participant has a rating on the C-SSRS ideation or behavior scales of 3 or above.• Participant has a recent history, or active clinically significant manifestations, of a metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eye / ears / nose / throat disorder, or any other acute or chronic condition that, in the Investigator’s opinion, would limit the participant’s ability to complete or take part in this study.• Participant has a history of treatment-resistant depression, as informed by the SAFER interview. Patients with non-response to 2 adequate antidepressant trials during the current major depressive episode, in the Investigator’s opinion, will be excluded.• Participant has a known allergy to Compound 1 or any of the excipients.• Participant has a current or previous history of psychosis, as per the Investigator’s assessment.• Participant has a history of seizures (note: a single febrile seizure in childhood is allowed).WSGR Docket No. 55776-729.601• Participant has a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder.• Participant has a history of alcohol or drug dependence or use of psychedelics within 12 months prior to screening (note: if the participant uses recreational substances including marijuana or tetrahydrocannabinol -containing products, they must have a negative drug screen at baseline).• Participant has been treated or randomized in any other study using Compound 1.• Participant is using an inhibitor of CYP2D6 within 14 days or 5 half-lives (whichever is longer), and / or inducer of CYP2D6 within 3 weeks prior to receiving the first dose of study drug.• Participants must not take any CYP2D6 inhibitors or inducers during the study.• Participant has a history of significant childhood adversity, as assessed using the Adverse Childhood Experience Questionnaire (ACE-Q) completed during screening and determined qualitatively by the Investigator.• Participant is unwilling to comply with all caffeine and nicotine restrictions as directed by site and Investigator.Example 6: Quantitative Electroencephalogram

[0155] During the study, qEEG recordings were obtained under the supervision of trained research staff. A 10-minute qEEG recording was made with a 64-channel EEG acquisition system. The recording requires the participant to remain in resting condition for 5 minutes with eyes closed followed by 5 minutes with eyes open while looking at a fixed target. Absolute and relative powers were derived from artefact-free EEG signal considering the International Pharmaco-EEG Society 2012 definition of standard frequency bands. An increase in slow-wave theta activity was observed on qEEG.Example 7: Polysomnography.

[0156] During the study, PSG recordings of sleep parameters were obtained under the supervision of trained research staff. The participants underwent full overnight PSG from night time (approximately 23:00) until waking up. The PSG includes 6-channel EEG, 2-channel electromyography (EMG), two electrooculogram to record eye movements, and an ECG. Relevant outcomes were sleep staging (hypnogram) and a variety of parameters related to sleep macro structure and SWA. An increase in slow wave density during NREM was observed on PSG Slow Wave Density (SWD) increased across all measured regions during NREM as observed on PSG on the first night after Compound 1 administration (FIG. 22). SWD is one of several parameters used to describe SlowWSGR Docket No. 55776-729.601Wave Activity (SWA). Bar graphs show mean + / - SEM of all participants. To assess drug effect and reduce intersubject variability, individual values were divided by value measured on Night -1 .

[0157] These pharmacodynamic signals, such as qEEG and PSG, are emerging markers of cortical plasticity and synaptic strength (Duncan et al., 2013) and have been shown to correlate with the activity of other known plastogens, including ketamine.Example 8: A Phase 2, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Compound 1 in the Treatment of Adult Participants with Major Depressive Disorder

[0158] This example illustrates a Phase II study to evaluate safety, tolerability, and efficacy of neuroplastogen Compound 1 in the treatment of adult participants with major depressive disorder.

[0159] Study Methodology: A 3-arm, randomized, double-blind, parallel-group, placebo- controlled study, with participants randomized 1 : 1 : 1 to oral Compound 1 once a day, oral Compound 1 intermittent dosing 3 times per week (with oral placebo on the other days to maintain the study blinding), or oral placebo once a day. Compound 1 dose in all 3 arms will be dependent on the CYP2D6 activity score (AS) (collected from a sample taken during the screening period), with participants being classified as low (AS score = 0.25 to 0.75), intermediate (AS score = 1.0 to 1.5) or high (AS score = 1.75 to 2.25) activity. The low AS group will take a dose of 50 mg, the intermediate AS group will take a dose of 100 mg, and the high AS group will take a dose of 200 mg). The study will include a 4-week screening period, a 4-week treatment period, and a follow-up period. The study will be conducted on an outpatient basis. An overview of the study plan is provided in FIG. 20.

[0160] Alternate Study Methodology: A 3-arm, randomized, double-blind, parallel-group, placebo-controlled study, with participants randomized 1: 1 : 1 to oral Compound 1 once a day, oral Compound 1 intermittent dosing 3 times per week (with oral placebo on the other days to maintain the study blinding), or oral placebo once a day. Compound 1 dose in all 3 arms will be dependent on the CYP2D6 activity score (AS) (collected from a sample taken during the screening period), with participants being classified as low (AS score = 0.25), intermediate (AS score 0.5 to 1.25) or high (AS score = 1.5 to 2.25) activity. The low AS group will take a dose of 75 mg, the intermediate AS group will take a dose of 150 mg, and the high AS group will take a dose of 300 mg). The study will include a 4-week screening period, a 4-week treatment period, and a follow-up period. The study will be conducted on an outpatient basis.

[0161] Screening Period: The screening period begins with the signing of the informed consent form (ICF). Participants will be assessed against the inclusion / exclusion criteria, with eligibilityWSGR Docket No. 55776-729.601 confirmed by a central review process. If determined that they are likely to be eligible, a blood sample will be taken for genetic testing to determine CYP2D6 activity. If the participant is currently receiving antidepressant pharmacotherapy, this must be stopped sufficiently prior to the start of the screening period (based on the half-life of the antidepressant pharmacotherapy) to ensure that the participant is fully weaned off before the Day 1 baseline assessments are conducted.

[0162] Treatment Period: Eligible participants will complete the baseline assessments in-clinic on Day 1. Participants will be categorized as either low, intermediate, or high AS for CYP2D6 based on the results of the screening genetic sample. Participants will be randomized to 1 of 3 treatment arms (Compound 1 once daily, Compound 1 intermittent dosing 3 times a week, or placebo once daily) in a 1 : 1 : 1 ratio within each AS group.

[0163] Participants will self-administer the study intervention to which they are randomized on the morning of each day (participants randomized to intermittent dosing will receive a placebo capsule on the days they are not receiving Compound 1 to maintain the study blind). Participants will be instructed not to take their morning dose on days that they attend clinic - they will be given a new treatment pack at clinic once all of the assessments have been completed, and will take the first dose of the new pack in clinic. Prior to taking the first dose of study treatment on Day 1, a Placebo-Control Reminder Script (a brief interactive procedure that educates participants about factors known to cause placebo response (Cohen et al., Neuropsychopharmacology. Volume 46, pages 844-850 (2021))) will be read out. A member of the Investigator’s team will contact the participant in between visits where possible to check on their welfare. Once the participant has finished the 4-week treatment period, an end-of-treatment (EOT) visit will be conducted.

[0164] Follow-up Period: A follow-up visit will be conducted after the EOT visit. During this time participants should not start any new antidepressant medications. If a participant is in urgent need of new antidepressant pharmacotherapy during this time, the follow-up visit should be conducted before the new antidepressant medication(s) are started.Example 9: Phase II study objectives and endpoints

[0165] Objectives: Primary:• The primary efficacy objective for the study is to determine if treatment with Compound 1 oral capsules reduces depressive symptoms in participants with MDD compared to matching placebo, as rated on the Montgomery -Asberg Depression Rating Scale (MADRS).

[0166] Objectives: Secondary:• To determine if treatment with Compound 1 oral capsules reduces depressive symptoms in participants with MDD using additional efficacy assessments.WSGR Docket No. 55776-729.601

[0167] Objectives: Safety:• To evaluate the safety and tolerability of Compound 1 oral capsules using daily dosing and intermittent dosing.

[0168] Objectives: Pharmacokinetic:• To confirm the PK of Compound 1 oral capsules in plasma samples.

[0169] Endpoints: Primary• Reduction in depressive symptoms from baseline to the end of treatment (EOT) following Compound 1 administration once daily and Compound 1 intermittent dosing compared to placebo, as rated on the MADRS.

[0170] Endpoints: Secondary• To evaluate the change from baseline to EOT following Compound 1 administration once daily and following Compound 1 intermittent dosing compared to placebo, as assessed using one or more of the following tools: o Clinician-Administered Dissociative States Scale (CADSS) o Hamilton Rating Scale for Depression (HAM-D) o Hamilton Anxiety Rating Scale (HAM-A) o Clinical Global Impression - Improvement (CGI-I) o Clinical Global Impression - Severity (CGI-S) o 36-item short form survey (SF-36) o Patient health questionnaire - 9 questions (PHQ-9) o EuroQol Standardized Health Questionnaire (5-level) (EQ-5D-5L) o Cambridge Neuropsychological Test Automated Battery (CANTAB), including Psychomotor Vigilance Test (PVT), Cognition Kit N-Back test (N-Back), paired associates learning (PAL) and emotional bias task (EBT).

[0171] Endpoints: Safety• To assess the frequency and severity of adverse events (AEs), and changes from baseline in physical examination, clinical laboratory measures, vital signs, and ECGs for daily and intermittent Compound 1 dosing compared to placebo. Change from baseline in the Columbia Suicide Severity Rating Scale (C-SSRS) will also be assessed as a safety measure.

[0172] Endpoints: Pharmacokinetic• To evaluate the PK of Compound 1 using PK samples collected approximately 4 hours after dosing on Day 1 (the approximate time of the maximum plasma concentration (Tmax) of Compound 1) and EOT.WSGR Docket No. 55776-729.601Example 10: Phase II study population

[0173] Inclusion criteria:• Participant has signed an ICF prior to any study-specific procedures being performed.• Participant is an ambulatory male or female between 18 and 65 years of age, inclusive.• Participant is in good physical health and has no clinically significant findings, as determined by the Investigator, on physical examination, 12-lead electrocardiogram (ECG), or clinical laboratory tests.• Participant agrees to adhere to study requirements.• Participant has a diagnosis of major depressive disorder (MDD) that has been present for at least a 12-week period (up to a maximum of 2 years for the current episode), as diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders (SCID-I).• Participant has a Hamilton Rating Scale for Depression, 17-item (HAM-D) total score of >22 at screening and Day 1 (prior to dosing).• Participant is willing to delay start of other antidepressant or antianxiety medications and any new pharmacotherapy agents, including as-needed agents, during the study (from screening to the end of the follow-up period). (Note: up to 1 mg / day of lorazepam is allowed, as needed, to help with breakthrough symptoms such as anxiety or trouble falling asleep).• Participant agrees to practice an acceptable method of highly effective birth control at screening and throughout study participation. Highly effective methods of birth control include sexual abstinence (for males and females); vasectomy; or a condom with spermicide in combination with a highly effective female partner’s method (for males); and hormonal methods of contraception (i.e., established use of oral, implantable, injectable, or transdermal hormones); placement of an intrauterine device; placement of an intrauterine system; and mechanical / barrier method of contraception (i.e., condom or occlusive cap [diaphragm or cervical / vault cap] in conjunction with spermicide [foam, gel, film, cream, or suppository]) (for females).

[0174] Exclusion criteria:• Participant is a cytochrome P450 CYP2D6 poor- or ultra-metabolizer, as defined by an Activity Score (AS) of 0 or >2.25.• Participant has a history of suicide attempt in the last 2 years (this will be determined as part of the MDD diagnosis using the SCID-I).• Participant has a rating on the C-SSRS ideation or behavior scales of 3 or above.• Participant has a recent history or active clinically significant manifestations of a metabolic,WSGR Docket No. 55776-729.601 hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eye / ears / nose / throat disorder, or any other acute or chronic condition that, in the Investigator’s opinion, would limit the participant’s ability to complete or take part in this clinical study.• Participant has a history of treatment -resistant depression, evaluated using the ATRQ questionnaire (Chandler et al., CNS Neuroscience & Therapeutics. Volume 16, pages 322-324 (2010))• Participant has a known allergy to Compound 1 or related compounds.• Participant has a positive pregnancy test at screening or on Day 1 prior to the start of study drug administration.• Participant has detectable hepatitis B surface antigen (HbsAg), anti-hepatitis C virus (HCV), or human immunodeficiency virus (HIV) antibody at screening.• Participant has a current or previous history of psychosis, as per the Investigator’ s assessment.• Participant has a history of seizures (note: a single febrile seizure in childhood is allowed).• Participant has a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder.• Participant has a history of alcohol or drug dependence or use of psychedelics within 12 months prior to screening (note: if the participant uses marijuana, they must be willing to stop so they can achieve a negative drug screen at screening).• Participant has had exposure to another investigational medication or device within 5 half-lives and not less than 30 days prior to screening.• Participant has been treated or randomized in any other study using Compound 1.• Participant is receiving concomitant psychotropic medications. Note: sleep aids and hypnotics are allowed.• Participant is using a strong inhibitor and / or inducer of cytochrome P450 (CYP)2D6 within 14 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study drug. Participants must not take any CYP2D6 inhibitors during the study.Example 11: Effects of Compound 1 on Delta and Theta power as measured with EEG

[0175] EEG data represent electrical voltage differences between pairs of recording electrodes placed on the scalp. These electrical signals are caused by the summated electrical activity of excitatory and inhibitory postsynaptic potentials impinging on cortical pyramidal cell. Because of the insulating effects of the skull, scalp, and CSF, and the small intensity of the currents, extensive temporal and spatial summation of activity is necessary before neuronal electrical activity can be detected on the scalp.WSGR Docket No. 55776-729.601

[0176] Resting-state EEG recordings with open and closed eyes for 4 min in each eye state were performed. Each recording employed alternating periods with eyes open and closed with a duration of 64-seconds for each period. Subjects were positioned in a semi -recumbent position facing a featureless wall and were instructed not to stare, not to move their head and eyes, and to suppress eye blinks.

[0177] EEG was continuously recorded before and after administering Compound 1 using a 40- channel recording system (Refa-40, TMSi B.V., the Netherlands). Electrodes were placed according to the international 10-20 system (32-lead cap, TMSi B.V.). The results of the EEG study are shown in FIG. 16A-16D. FIG. 16A shows an increase in Delta wave power post treatment with Compound 1. 20mg of Compound 1 increased Delta wave power by >26pp 305 minutes after administration. 60mg of Compound 1 increased Delta wave power by >26pp 101 to 305 minutes after administration. 120 mg of Compound 1 increased Delta wave power by >26pp at 63 minutes after administration, by >58pp 101 to 213 minutes after administration, and by >26pp 305 minutes after administration. Placebo control did not significantly increase Delta wave power at any timepoint.

[0178] FIG. 16B shows an increase in Theta wave power post treatment with Compound 1. 2mg of Compound 1 increased Theta wave power by >26pp 488 minutes after administration. 6mg of Compound 1 increased Theta wave power by >26pp 63, 213, and 305 minutes after administration. 20mg of Compound 1 increased Theta wave power by >26pp 63 and 213 minutes after administration. 60 mg of Compound 1 increased Theta wave power by >26pp 63 minutes after administration, by > 58pp 101 minutes after administration, and by >26pp 213 and 305 minutes after administration. 120mg of Compound 1 increased Theta wave power by >58pp 63, 101, and 213 minutes after administration, and >26pp 305 and 488 minutes after administration. Placebo control increased Theta wave power by >26pp 101 minutes after administration.

[0179] FIG. 16C shows an increase in Delta wave power post treatment with Compound 1, sorted by Cmax. 2 mg Compound 1 achieved a Cmax of 0.9 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and did not significantly increase delta band power. 6 mg Compound 1 achieved a Cmax of 1.4 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >11.8pp 1 hour, 3.5 hours, and 5 hours after administration. 20 mg Compound 1 achieved a Cmax of 12 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >11.8pp 5 hours after administration. 60 mg Compound 1 achieved a Cmax of 31 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >5.9pp 1 hour, >5.9pp 1 hour 40 minutes, >11.8pp 3.5 hours, and >11.8pp 5 hours after administration. 50 mgWSGR Docket No. 55776-729.601Compound 1 achieved a Cmax of 33 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >11.8pp 3.5 hours, and >5.9pp 5 hours after administration. 100 mg Compound 1 achieved a Cmax of 38.7 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >11.8pp Ihour, >11.8pp 1 hour 40 minutes, >11.8pp 3.5 hours, >11.8pp 5 hours, and >11.8pp 8 hours, after administration. 120 mg Compound 1 achieved a Cmax of 60.9 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >5.9pp Ihour, >11.8pp 3.5 hours, and >5.9pp 5 hours after administration. 220 mg Compound 1 achieved a Cmaxof 64 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 2.0 and increased Delta band power by >5.9pp Ihour, >11.8pp Ihour 40 minutes, >5.9pp 3.5 hours, and >5.9pp 5 hours after administration. 120 mg Compound 1 achieved a Cmaxof 73 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Delta band power by >17.7pp Ihour, >17.7pp Ihour 40 minutes, >17.7pp 3.5 hours, >11.8pp 5 hours, and >11.8pp 8 hours after administration. 360 mg Compound 1 achieved a Cmaxof 111 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 2.0 and increased Delta band power by >5.9pp Ihour after administration. 350 mg Compound 1 achieved a Cmaxof 112 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 2.0 and increased Delta band power by >11.8pp Ihour 40 minutes, >11.8pp 3.5 hours, >11.8pp 5 hours, and >5.9pp 8 hours after administration. 160 mg Compound 1 achieved a Cmaxof 169 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 1.0- 1.25 and increased Delta band power by >5.9pp Ihour, >17.7pp 3.5 hours, >17.7pp 5 hours, and >11.8pp 8 hours after administration.

[0180] FIG. 16D shows an increase in Theta wave power post treatment with Compound 1, sorted by Cmax. 2 mg Compound 1 achieved a Cmaxof 0.9 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased theta band power by >7.5pp 1 hour, >7.5pp 1 hour 40 minutes, >7.5pp 3.5 hours, >7.5pp 5 hours, and >15. Opp 8 hours after administration. 6 mg Compound 1 achieved a Cmaxof 1.4 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power by >15pp 1 hour, >15pp 1 hour 40 minutes, >15pp 3.5 hours, and >15pp 5 hours after administration. 20 mg Compound 1 achieved a Cmaxof 12 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and did not significantly increase theta band power after administration. 60 mg Compound 1 achieved a Cmaxof 31 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power by >7.5pp 1 hour, >15. Opp 1 hour 40 minutes, >15. Opp 3.5 hours, and >15. Opp 5 hours after administration. 50 mg Compound 1 achieved a Cmaxof 33 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power byWSGR Docket No. 55776-729.601>15. Opp 3.5 hours, and >15. Opp 5 hours, and >7.5pp 8 hours after administration. 100 mg Compound 1 achieved a Cmax of 38.7 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power by >7.5pp 1 hour 40 minutes, >15. Opp 3.5 hours, >15. Opp 5 hours, and >15. Opp 8 hours after administration. 120 mg Compound 1 achieved a Cmax of 60.9 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power by >7.5pp Ihour, >7.5pp 3.5 hours, and >7.5pp 5 hours after administration. 220 mg Compound 1 achieved a Cmax of 64 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 2.0 and increased Theta band power by >15. Opp Ihour, >22.5pp Ihour 40 minutes, >15. Opp 3.5 hours, >15. Opp 5 hours, >15. Opp 8 hours, and >7.5pp 24 hours after administration. 120 mg Compound 1 achieved a Cmax of 73 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 0.25-2.0 and increased Theta band power by >22.5pp Ihour, >22.5pp Ihour 40 minutes, >15. Opp 3.5 hours, >15. Opp 5 hours, and >15. Opp 8 hours after administration. 360 mg Compound 1 achieved a Cmax of 111 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 2.0 and increased Theta band power by >7.5pp 8 hours after administration. 350 mg Compound 1 achieved a Cmax of 112 ng / mL in subjects in the MAD cohort with a CYP2D6 activity score of 2.0 and increased Theta band power by >15. Opp Ihour 40 minutes, >15. Opp 3.5 hours, >15. Opp 5 hours, and >7.5pp 8 hours after administration. 160 mg Compound 1 achieved a Cmax of 169 ng / mL in subjects in the SAD cohort with a CYP2D6 activity score of 1.0-1.25 and increased Theta band power by >15. Opp Ihour, >22.5pp 3.5 hours, >22.5pp 5 hours, >22.5pp 8 hours, and >15pp 24 hours after administration.Example 12: In Vitro Metabolite Identification

[0181] The purpose of this study was to determine the metabolism of Compound 1 using cryopreserved hepatocytes from CD-I mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkey, and human using cold bioanalytical methodology.Methods

[0182] Cryopreserved hepatocytes from the 5 species were prepared and treated using standard methods as described by the vendor. The percentage of viable cells in the suspensions was determined using the Trypan Blue stain method to ensure a minimum viability of at least 70% which was met.

[0183] Compound 1 (10 pM) was incubated in a 12- or 24-well plate containing hepatocyte suspensions from each species (1 million viable cells / mL) at 37°C for 4 hours under 5% CO2 and 95% air. Incubation of Compound 1 in the presence of incubation media alone (no hepatocytes) was also conducted to evaluate non-enzymatic degradation. Verapamil (1.0 pM) was used as a positive control under the same conditions described above. An aliquot from each hepatocyteWSGR Docket No. 55776-729.601 suspension was analyzed by LC / UV / MS to obtain metabolite profiles. Metabolites, including those resulting from phase 1 or phase II metabolic pathways, were identified and characterized by LC / UV, LC / MS, and MS / MS. Mass spectral analysis was conducted using an LTQ / Orbitrap mass spectrometer.Results

[0184] The relative abundance of Compound 1 and its proposed metabolites in mouse, dog, monkey, and human hepatocytes after 3 -hr incubation are shown in Table 1 below.Table 4WSGR Docket No. 55776-729.601Example 13: Reaction Phenotyping; metabolic stability following incubation in recombinant cytochrome P450 enzymes in human liver microsomes

[0185] The objectives of the study were to identify the cytochrome P450 (CYP) enzymes and additional enzymes systems where relevant that are responsible for the metabolism of Compound 1. In addition, to evaluate the relative contribution of each enzyme to the metabolic clearance of Compound 1.Methods

[0186] Incubations of Compound 1 were carried out individually with recombinant CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 and 3A5 for 90 minutes using an enzyme concentration of 100 pmol / mL in human liver microsomes (HLM). The incubation mixture (total volume of 1 mL) contained Compound 1 (1 pM), MgC12 (3 mM), rCYP (100 pmol / mL) in 0.1 M phosphate buffer (pH 7.4). The reaction mixture was placed in a shaking water bath kept at 37°C and pre-incubated for 5 minutes before the addition of NADPH (2 mM) and then incubated for further 90 minutes. Aliquots were taken in duplicate at 0, 5, 10, 15, 30, 60, and 90 minutes and assayed by LC-MS / MS. The chemical inhibition studies were conducted with standard inhibitors for each recombinant CYP. Incubations were carried out for 90 minutes with HLM at 1 mg / mL and the standard inhibitors. Control incubations contained solvents used for making inhibitor solutions. All samples were assayed by LC-MS / MS. The metabolite profiles of Compound 1 in HLM and 2 of the recombinant CYP enzymes with high activity were also determined in order to further characterize specific CYP450 enzyme inhibition. In vitro metabolic half-life was estimated using linear regression and intrinsic clearance was calculated using standard methods.Results

[0187] Metabolic stability of Compound 1 in the presence of the 8 different recombinant CYP450 enzymes is presented in Table 2 below and the numbers represent % Compound 1 remaining at the indicated time.Table 5WSGR Docket No. 55776-729.601

[0188] Compound 1 was rapidly metabolized by recombinant CYP 2D6, 2B6, 2C19 and more slowly in the presence of recombinant CYP1 A2. However, when taking human liver abundance of all of the metabolically active CYP’s into account, CYP2D6 represented about 93% of all estimated CYP450 enzyme related activity. Notably, little or no CYP3 A4 metabolic activity was found.

[0189] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WSGR Docket No. 55776-729.601CLAIMSWe Claim:

1. A method of treating a neuropsychiatric disease or disorder in an individual in need thereof, comprising administering to the individual about 1 mg to about 500 mg of Compound 1 calculated by free base:Compound 1.2 The method of claim 1, wherein Compound 1 is administered to the individual daily.3 The method of claim 1, wherein Compound 1 is administered once every 2 days.4 The method of claim 1, wherein Compound 1 is administered once every 3 days.5 The method of claim 1, wherein Compound 1 is administered 3 times a week.6 The method of claim 1, wherein Compound 1 is administered for at least 3 days, or for at least 5 days, or for at least 7 days, or for at least 10 days, or for at least 14 days, or for at least 21 days, or for at least 28 days.7 The method of claim 1, wherein Compound 1 is administered once every 7 days.8 The method of any one of claims 1-7, wherein Compound 1 is administered orally.9 The method of any one of claims 1-8, comprising administering about 50 mg to about 360 mg of Compound 1 calculated by free base.10 The method of any one of claims 1-8, comprising administering about 1 mg to about 10 mg of Compound 1 calculated by free base.11 The method of claim 10, comprising administering about 2 mg of Compound 1 calculated by free base.12 The method of claim 10, comprising administering about 6 mg of Compound 1 calculated by free base.13 The method of claim 10, comprising administering about 10 mg of Compound 1 calculated by free base.14 The method of any one of claims 1-8, comprising administering about 10 mg to about 30 mg of Compound 1 calculated by free base.15 The method of claim 14, comprising administering about 20 mg of Compound 1 calculated by free base.WSGR Docket No. 55776-729.60116. The method of any one of claims 1-8, comprising administering about 30 mg to about 100 mg of Compound 1 calculated by free base.

17. The method of claim 16, comprising administering about 50 mg of Compound 1 calculated by free base.

18. The method of claim 16, comprising administering about 100 mg of Compound 1 calculated by free base.

19. The method of any one of claims 1-8, comprising administering about 60 mg to about 90 mg of Compound 1 calculated by free base.

20. The method of claim 19, comprising administering about 60 mg of Compound 1 calculated by free base.

21. The method of claim 19, comprising administering about 75 mg of Compound 1 calculated by free base.

22. The method of claim 19, comprising administering about 80 mg of Compound 1 calculated by free base.

23. The method of claim 19, comprising administering about 90 mg of Compound 1 calculated by free base.

24. The method of any one of claims 1-8, comprising administering about 100 mg to about 250 mg of Compound 1 calculated by free base.

25. The method of claim 24, comprising administering about 160 mg of Compound 1 calculated by free base.

26. The method of claim 24, comprising administering about 200 mg of Compound 1 calculated by free base.

27. The method of claim 24, comprising administering about 220 mg of Compound 1 calculated by free base.

28. The method of any one of claims 1-8, comprising administering about 120 mg to about 180 mg of Compound 1 calculated by free base.

29. The method of claim 28, comprising administering about 120 mg of Compound 1 calculated by free base.

30. The method of claim 28, comprising administering about 150 mg of Compound 1 calculated by free base.

31. The method of claim 28, comprising administering about 170 mg of Compound 1 calculated by free base.

32. The method of claim 28, comprising administering about 180 mg of Compound 1 calculated by free base.WSGR Docket No. 55776-729.60133. The method of any one of claims 1-8, comprising administering about 240 mg to 360 mg of Compound 1 calculated by free base.

34. The method of claim 33, comprising administering about 240 mg of Compound 1 calculated by free base.

35. The method of claim 33, comprising administering about 250 mg of Compound 1 calculated by free base.

36. The method of claim 33, comprising administering about 300 mg of Compound 1 calculated by free base.

37. The method of claim 33, comprising administering about 350 mg of Compound 1 calculated by free base.

38. The method of claim 33, comprising administering about 360 mg of Compound 1 calculated by free base.

39. The method of any one of claims 1-8, wherein the individual has an activity score (AS) based on the cytochrome P450 2D6 (CYP2D6) genetic profile.

40. The method of claim 39, wherein the individual has an AS from 0.25 to 0.5±0.25 and the individual is administered a dose of about 50 mg Compound 1 calculated by free base.

41. The method of claim 39, wherein the individual has an AS from 0.25 to 0.5±0.25 and the individual is administered a dose of about 60 mg to about 90 mg of Compound 1 calculated by free base.

42. The method of claim 39, wherein the individual has an AS from 0.75±0.25 to 1.25±0.25 and the individual is administered a dose of about 100 mg Compound 1 calculated by free base.

43. The method of claim 39, wherein the individual has an AS from 0.75±0.25 to 1.25±0.25 and the individual is administered a dose of about 120 mg to about 180 mg of Compound 1 calculated by free base.

44. The method of claim 39, wherein the individual has an AS from 1.5±0.25 to 2.25 and the individual is administered a dose of about 200 mg Compound 1 calculated by free base.

45. The method of claim 39, wherein the individual has an AS from 1.5±0.25 to 2.25 and the individual is administered a dose of about 240 mg to about 360 mg of Compound 1 calculated by free base.

46. The method of claim 39, wherein the individual has an AS of 0.25 and the individual is administered a dose of about 100 mg Compound 1 calculated by free base.

47. The method of claim 39, wherein the individual has an AS from 0.5 to 1.25 and the individual is administered a dose of about 150 mg Compound 1 calculated by free base.WSGR Docket No. 55776-729.60148. The method of claim 39, wherein the individual has an AS from 0.5 to 1.25 and the individual is administered a dose of about 170 mg Compound 1 calculated by free base.

49. The method of claim 39, wherein the individual has an AS from 0.5 to 0.75 and the individual is administered a dose of about 150 mg Compound 1 calculated by free base.

50. The method of claim 39, wherein the individual has an AS from 1.5 to 2.25 and the individual is administered a dose of about 250 mg Compound 1 calculated by free base.

51. The method of claim 39, wherein the individual has an AS from 1.0 to 2.25 and the individual is administered a dose of about 250 mg Compound 1 calculated by free base.

52. The method of any one of claims 1-51, wherein the neuropsychiatric disease comprises depression, addiction, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, or substance use disorder.

53. The method of any one of claims 1-51, wherein the neuropsychiatric disease comprises depression.

54. The method of any one of claims 1-51, wherein the neuropsychiatric disease is treatment resistant depression, major depressive disorder, suicidal ideation, or combinations thereof.

55. The method of any one of claims 1-51, wherein the neuropsychiatric disease comprises a major depressive disorder.

56. The method of any one of claims 1-55, wherein the individual demonstrates decreased depressive symptoms at the end of treatment compared to baseline, as measured by Montgomery-Asberg Depression Rating Scale (MADRS).

57. The method of claim 56, wherein the MADRS score is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

58. The method of any one of claims 1-57, wherein the individual demonstrates decreased depressive symptoms at the end of treatment compared to baseline, as measured by Clinician- Administered Dissociative States Scale (CADSS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression - Improvement (CGI-I), Clinical Global Impression - Severity (CGI-S), 36-item short form survey (SF-36), speech characteristics, Patient health questionnaire - 9 questions (PHQ-9), EuroQol Standardized Health Questionnaire (5 -level) (EQ-5D-5L), or Cambridge Neuropsychological Test Automated Battery (CANTAB), including Psychomotor Vigilance Test (PVT), Cognition Kit N-Back test (N-Back), paired associates learning (PAL) or emotional bias task (EBT).WSGR Docket No. 55776-729.60159. The method of any one of claims 1-58, wherein the individual demonstrates increased slow wave activity after administering Compound 1 compared to baseline prior to administering Compound 1, as measured by quantitative electroencephalographic (qEEG).

60. The method of claim 59, wherein the slow wave activity (e.g., delta band power or theta band power) is increased by at least about lOpp, at least about 20pp, at least about 30pp, at least about 40pp, at least about 50pp, at least about 60pp, at least about 70pp, at least about 80pp, at least about 90pp, or at least about lOOpp between 0 to 24 hours after administering Compound 1.

61. The method of any one of claims 1-60, wherein the administering does not cause hallucinations, dissociative effects, or psychomimetic effects.

62. The method of claim 61, wherein the administering does not cause hallucinations, dissociative effects, or psychomimetic effects as determined by a Clinician-Administered Dissociative States Scale (CDSS), a Bond-Lader Visual Analog Scale (VAS), a Bowdle VAS, or a Revised Mystical Experience Questionnaire (MEQ-30), or a combination thereof.

63. The method of claim 62, wherein the CADSS value is less than 5, or is less than 3, or is less than 2, or is less than 1.

64. The method of claim 62 or 63, wherein the CADSS value is less than 5, or is less than 3, or is less than 2, or is less than 1 at any point after administering Compound 1.

65. The method of claim 62, wherein the Bond-Lader VAS value is between 25-75, or is between 30-70, or is between 35-65 for each measure on the scale.

66. The method of claim 62 or 65, wherein the Bond-Lader VAS value is between 25-75, or is between 30-70, or is between 35-65 for each measure on the scale at any point after administering Compound 1.

67. The method of any one of claims 1-66, wherein the administering does not cause cardiotoxicity.

68. The method of any one of claims 1-67, wherein a risk of the individual developing any serious treatment-emergent adverse event (TEAE) after the administering is less than about 60%, or less than about 50%, or less than about 40%, or less than about 30%, or less than about 20%, or less than about 10%, or less than about 5%.

69. The method of any one of claims 1-68, wherein the individual is fasted prior to the administering of Compound 1.

70. The method of any one of claims 1-68, wherein the individual is sated prior to the administering of Compound 1.

71. The method of any one of claims 1-68, wherein the individual is fasted or sated prior to the administering of Compound 1.WSGR Docket No. 55776-729.60172. A method of treating a neuropsychiatric disease in an individual in need thereof, comprising administering to the individual a dose of Compound 1 :Compound 1, wherein the individual has a cytochrome P4502D6 (CYP2D6) activity score (AS).

73. The method of claim 72, wherein the dose of Compound 1 correlates with the AS.

74. The method of claim 73, wherein:(a) the dose of Compound 1 increases when the AS increase; or(b) the dose of Compound 1 decreases when the AS decreases.

75. The method of claim 72, wherein the individual has a high AS; and Compound 1 is administered at a maximum tolerated dose.

76. The method of claim 72, wherein the individual has an intermediate AS; and Compound 1 is administered at a one-half maximum tolerated dose.

77. The method of claim 72, wherein the individual has a low AS; and Compound 1 is administered at a one-quarter maximum tolerated dose.

78. The method of claim 75, wherein the maximum tolerated dose of Compound 1 is about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, or about 360 mg calculated by free base.

79. The method of claim 76, wherein the one-half maximum tolerated dose is about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, or about 180 mg calculated by free base.

80. The method of claim 77, wherein the one-quarter maximum tolerated dose is about 50 mg, about 55 mg, about 60 mg, about 75 mg, about 80 mg, or about 90 mg calculated by free base.

81. The method of claim 72, wherein the individual has an AS of 0.25 and the individual is administered a dose of about 100 mg Compound 1 calculated by free base.

82. The method of claim 72, wherein the individual has an AS from 0.5 to 1.25 and the individual is administered a dose of about 150 mg Compound 1 calculated by free base.

83. The method of claim 72, wherein the individual has an AS from 0.5 to 1.25 and the individual is administered a dose of about 170 mg Compound 1 calculated by free base.

84. The method of claim 72, wherein the individual has an AS from 0.5 to 0.75 and the individual is administered a dose of about 150 mg Compound 1 calculated by free base.WSGR Docket No. 55776-729.60185. The method of claim 72, wherein the individual has an AS from 1.5 to 2.25 and the individual is administered a dose of about 250 mg Compound 1 calculated by free base.

86. The method of claim 72, wherein the individual has an AS from 1.0 to 2.25 and the individual is administered a dose of about 250 mg Compound 1 calculated by free base.

87. The method of any one of claims 1-86, wherein the individual has a diagnosis of major depressive disorder (MDD) that has been present for 12-weeks to 2 years.

88. The method of any one of claims 1-87, wherein the individual has a Hamilton Rating Scale for Depression, 17-item (HAM-D) total score of at least 14, such as at least 22, prior to administering Compound 1.

89. The method of any one of claims 1-88, wherein the individual does not have a cytochrome P450 2D6 (CYP2D6) activity score (AS) of less than 0.25 or greater than 2.25.

90. The method of any one of claims 1-89, wherein the individual does not have psychosis or a history of psychosis.

91. The method of any one of claims 1-90, wherein the individual does not have seizures or a history of seizures.

92. The method of any one of claims 1-91, wherein the individual does not have bipolar disorder, schizophrenia, and / or a schizoaffective disorder.

93. The method of any one of claims 1-92, wherein the individual does not have a history of alcohol or drug dependence or use of psychedelics within the 12 months prior to administering Compound 1.

94. The method of any one of claims 1-93, wherein the individual has not received therapy with a strong inhibitor, an inducer of cytochrome P450 (CYP)2D6, or both, within a period of time prior to administering Compound 1, and wherein the period of time is:(a) 14 days, when 5 half-lives of the strong inhibitor or the inducer is shorter than 14 days; or(b) 5 half-lives of the strong inhibitor or the inducer, when 5 half-lives of the strong inhibitor or the inducer is longer than 14 days.

95. The method of any one of claims 1-94, wherein Compound 1 is administered without a CYP2D6 inhibitor.

96. A pharmaceutical composition comprising about 1 mg to about 500 mg of Compound 1 calculated by free base.

97. The pharmaceutical composition of claim 96, wherein the composition comprises about 50 mg to about 200 mg of Compound 1 calculated by free base.

98. The pharmaceutical composition of claim 96, wherein the composition comprises about 2 mg, about 10 mg, or about 50 mg of Compound 1 calculated by free base.WSGR Docket No. 55776-729.60199. The pharmaceutical composition of claim 96, wherein the composition comprises about 50 mg, about 100 mg, or about 200 mg of Compound 1 calculated by free base.

100. The pharmaceutical composition of claim 96, wherein the composition comprises about 100 mg, about 150mg, or about 250 mg of Compound 1 calculated by free base.

101. The pharmaceutical composition of claim 96, wherein the composition comprises about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 240 mg, about 300 mg, or about 360 mg of Compound 1 calculated by free base.

102. The pharmaceutical composition of claim 96, wherein the composition comprises about 1 mg to about 10 mg of Compound 1 calculated by free base.

103. The pharmaceutical composition of claim 102, wherein the composition comprises about 2 mg of Compound 1 calculated by free base.

104. The pharmaceutical composition of claim 102, wherein the composition comprises about 6 mg of Compound 1 calculated by free base.

105. The pharmaceutical composition of claim 102, wherein the composition comprises about 10 mg of Compound 1 calculated by free base.

106. The pharmaceutical composition of claim 96, wherein the composition comprises about 10 mg to about 30 mg of Compound calculated by free base.

107. The pharmaceutical composition of claim 106, wherein the composition comprises about 20 mg of Compound 1 calculated by free base.

108. The pharmaceutical composition of claim 96, wherein the composition comprises about 30 mg to about 100 mg of Compound 1 calculated by free base.

109. The pharmaceutical composition of claim 108, wherein the composition comprises about 50 mg of Compound 1 calculated by free base.

110. The pharmaceutical composition of claim 108, wherein the composition comprises about 100 mg of Compound 1 calculated by free base.

111. The pharmaceutical composition of claim 96, wherein the composition comprises about 60 mg to 90 mg of Compound 1 calculated by free base.

112. The pharmaceutical composition of claim 111, wherein the composition comprises about 60 mg of Compound 1 calculated by free base.

113. The pharmaceutical composition of claim 111, wherein the composition comprises about 75 mg of Compound 1 calculated by free base.

114. The pharmaceutical composition of claim 111, wherein the composition comprises about 90 mg of Compound 1 calculated by free base.WSGR Docket No. 55776-729.601115. The pharmaceutical composition of claim 96, wherein the composition comprises about 100 mg to about 250 mg of Compound 1 calculated by free base.

116. The pharmaceutical composition of claim 115, wherein the composition comprises about 160 mg of Compound 1 calculated by free base.

117. The pharmaceutical composition of claim 115, wherein the composition comprises about 200 mg of Compound 1 calculated by free base.

118. The pharmaceutical composition of claim 115, wherein the composition comprises about 220 mg of Compound 1 calculated by free base.

119. The pharmaceutical composition of claim 96, wherein the composition comprises about 120 mg to 180 mg of Compound 1 calculated by free base.

120. The pharmaceutical composition of claim 119, wherein the composition comprises about 120 mg of Compound 1 calculated by free base.

121. The pharmaceutical composition of claim 119, wherein the composition comprises about 150 mg of Compound 1 calculated by free base.

122. The pharmaceutical composition of claim 119, wherein the composition comprises about 180 mg of Compound 1 calculated by free base.

123. The pharmaceutical composition of claim 96, wherein the composition comprises about 250 mg to 500 mg of Compound 1 calculated by free base.

124. The pharmaceutical composition of claim 96, wherein the composition comprises about 240 mg to 360 mg of Compound 1 calculated by free base.

125. The pharmaceutical composition of claim 124, wherein the composition comprises about 240 mg of Compound 1 calculated by free base.

126. The pharmaceutical composition of claim 124, wherein the composition comprises about 250 mg of Compound 1 calculated by free base.

127. The pharmaceutical composition of claim 124, wherein the composition comprises about 300 mg of Compound 1 calculated by free base.

128. The pharmaceutical composition of claim 124, wherein the composition comprises about 360 mg of Compound 1 calculated by free base.

129. The pharmaceutical composition of any one of claims 96-128, wherein the pharmaceutical composition is a tablet or a capsule.

130. The pharmaceutical composition of claim 129, wherein the pharmaceutical composition is a capsule.

131. The pharmaceutical composition of claim 129, wherein the pharmaceutical composition is a tablet.WSGR Docket No. 55776-729.601132. The pharmaceutical composition of any one of claims 96-131, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

133. The pharmaceutical composition of any one of claims 96-132, wherein the composition further comprises hypromellose and titanium dioxide.

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