WO2022235576A1

WO2022235576A1 - Methods and compositions for treating depression

Info

Publication number: WO2022235576A1
Application number: PCT/US2022/027308
Authority: WO
Inventors: Michael Z. Wang
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-05-03
Filing date: 2022-05-02
Publication date: 2022-11-10
Anticipated expiration: 2023-11-03

Abstract

Provided herein are methods and compositions related to administering dextrorphan to an individual in need of treatment of depression. Also provided herein are methods and compositions for inducing a dissociative experience in an individual or treating an individual who is experiencing depressive symptoms or who has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, and/or passive death wish.

Description

METHODS AND COMPOSITIONS FOR TREATING DEPRESSION

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/183,502, filed May 3, 2021, entitled “METHODS AND COMPOSITIONS FOR TREATING DEPRESSION,” the entire disclosure of which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION Provided herein are methods and compositions related to treating depression in an individual in need of such treatment.

BACKGROUND

Depression is a class of mental health disorders characterized by depressive symptoms or loss of interest in activities, causing significant impairment in daily life. Symptoms and signs of depression include persistent sadness, anxiety, “empty” mood; feelings of hopelessness or pessimism; irritability; feelings of guilt, worthlessness, or helplessness; loss of interest or pleasure in hobbies and activities; decreased energy or fatigue; and difficulty concentrating, remembering, or making decisions, among many other symptoms. The National Institute of Mental Health (NIMH) estimates that 17.3 million adults in the United States, or 7.1% of all adults in the United States, had at least one major depressive episode in 2017. The NIMH further estimates that depressive episodes were more common in females compared to males and that the prevalence of depressive episodes was highest among individuals aged 18-25. Examples of disorders characterized by depression include: major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectmm disorder, premenstrual dysphoric disorder, suicidal ideation, and passive death wish. There are many methods for treating depression and depressive symptoms, but additional approaches are needed. SUMMARY

The present disclosure relates, at least in part, to methods, compositions, and kits for inducing a dissociative experience in an individual by oral or intranasal administration to the individual an amount of dextrorphan that induces a dissociative experience within about 4 hours after administration (rapidly). It further relates to methods, compositions, and kits for treating depression in an individual in need of such treatment by orally or intranasally administering to the individual dextrorphan in an amount that induces a dissociative experience in the individual within about 4 hours after dextrorphan is administered. Described herein is a method of inducing a dissociative experience in an individual, such as a depressed individual or an individual with depressive symptoms, by oral or intranasal administration of dextrorphan. Also described is a method of treating depression by inducing, in an individual in need of such treatment, a dissociative experience by oral or intranasal administration of dextrorphan. In one embodiment, the method further comprises administering, to an individual who has undergone a dissociative experience induced by oral or intranasal administration of dextrorphan, one or more subsequent doses of dextrorphan (one or more doses of dextrorphan that do not induce a dissociative experience).

The method described is useful in treating a wide range of mental health disorders associated with depressive mood, depression, or depressive symptoms and potentially especially useful for individuals whose depressive mood, depression, or depressive symptoms are unresponsive to other forms of therapy and individuals at risk of attempting suicide. This method provides a new approach for treating depression, which can be of great value in the fields of psychiatry and neuroscience.

Aspects of the disclosure relate to a method of inducing a dissociative experience in an individual, comprising orally administering to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration.

Aspects of the disclosure relate to a method of inducing a dissociative experience in an individual, comprising intranasal administration to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration. Aspects of the disclosure relate to a method of treating depression in an individual, comprising orally administering, to an individual in need of treatment of depression, an amount of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours after administration. Aspects of the disclosure relate to a method of treating depression in an individual, comprising administering, intranasally, to an individual in need of treatment of depression, an amount of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours after administration.

Aspects of the disclosure relate to a method for treating depression in an individual, comprising orally administering a subsequent dose of dextrorphan to the individual, wherein the individual has previously experienced a dissociative experience induced by dextrorphan and is administered orally the subsequent dose of dextrorphan in an amount from about 15mg to about lOOmg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different dmg(s) to reduce depression in the individual.

Aspects of the disclosure relate to a pharmaceutical composition for treating depression in an individual, comprising a single oral dose of dextrorphan in an amount from about 150mg to about 600mg and a pharmaceutically acceptable excipient.

Aspects of the disclosure relate to a pharmaceutical composition for treating depression in an individual, comprising a single intranasal dose of dextrorphan in an amount from about 50mg to about 350mg and a pharmaceutically acceptable excipient.

Aspects of the disclosure relate to a pharmaceutical kit for treating depression in an individual, comprising a package containing single oral dosage forms of an amount of dextrorphan from about 15mg to about 600mg in each single dosage form, wherein each dosage form is separately contained in a different compartment in the package and instructions for oral administration indicate not more than one dose daily.

Aspects of the disclosure relate to a method of inducing a dissociative experience in an individual as measured by a Clinician-Administered Dissociative States Scale (CADSS) score, comprising orally or nasally administering to the individual an amount of dextrorphan such that an individual reports a CADSS score of 1-5 within 1.5 hours after administration.

In some embodiments, the dextrorphan is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is tartrate. In some embodiments, the dextrorphan is administered in the form of a composition comprising dextrorphan. In some embodiments, the composition further comprises an additional therapeutic agent.

Each of the limitations of the invention can encompass various embodiments of the invention. It is, therefore, anticipated that each of the limitations of the invention involving any one element or combinations of elements can be included in each aspect of the invention. This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used in this disclosure is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,”

“containing,” “involving,” and variations of thereof in this disclosure, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, and also from the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented in this disclosure. The accompanying drawings are not intended to be drawn to scale. The drawings are illustrative only and are not required for enablement of the disclosure. For purposes of clarity, not every component may be labeled in every drawing. In the drawings:

FIG. 1 depicts a graph showing pharmacokinetic data of dextrorphan following oral and nasal administration. Lines on the graph represent two separate trials of dextrorphan administered orally at 150 mg and dextrorphan administered nasally at 60 mg. The serum concentration of dextrorphan measured in nanograms per milliliter (ng/mL) is presented on the Y-axis. Time measured in minutes is presented on the X-axis.

FIG. 2 depicts a graph showing Clinician- Administered Dissociative States Scale (CADSS) data measured following oral and nasal administration of dextrorphan. Lines on the graph represent dextrorphan administered orally at 50 mg, two separate trials of dextrorphan administered orally at 150 mg, dextrorphan administered orally at 300 mg, dextrorphan administered orally at 600 mg, dextrorphan administered orally at 750 mg, and dextrorphan administered nasally at 60 mg. The CADSS score measured following oral and nasal administration of dextrorphan is presented on the Y-axis. Time measured in minutes is presented on the X-axis.

DETAILED DESCRIPTION

One aspect of the present disclosure is a method of inducing a dissociative experience in an individual by oral or intranasal administration of an amount or a dose of dextrorphan sufficient to cause/result in a dissociative experience in the individual within about 4 hours. The method has applicability across a wide age range, including adults and younger individuals. For example, the method can be carried out to induce a dissociative experience in an adult (a person who is aged at least 16 years) who is in need of or who would benefit from a dissociative experience as a therapy or to induce a dissociative experience in an adolescent or child (any person under the age of 16 years) who is in need of or who would benefit from a dissociative experience as a therapy. The individual is a person who is experiencing depressive symptoms or who has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish. The method comprises orally or intranasally administering an amount or a dose of dextrorphan sufficient to induce a dissociative experience in an individual within about 4 hours. In one embodiment, the amount or dose administered orally is from about 150 mg to about 600 mg. In some embodiments, the amount or dose administered orally is from about 200 mg to about 500 mg. In some embodiments, the amount or dose administered orally is from about 250 mg to about 300 mg. In some embodiments, the amount or dose administered orally is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In some embodiments, the amount or dose administered intranasally is from about 50 mg to about 350 mg. In some embodiments, the amount or dose admini tered intranasally is from about 100 mg to about 300 mg. In some embodiments, the amount or dose administered intranasally is from about 150 mg to about 250 mg. In some embodiments, the amount or dose administered intranasally is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg. The amount or dose is ingested or administered at one time (in a single administration), such that the entire amount of the oral or intranasal dose is ingested or administered in a short time, such as within ten minutes or less (e.g., within five minutes) after the beginning of administration. Oral administration refers to a route of administration in which a substance is taken through the mouth. Oral administration may also be referred to as “per os” or “P.O.” Intranasal administration refers to a route of administration in which a substance is sprayed into the nasal passage or contacted with the nasal cavity of an individual.

The term dissociative experience is recognized in the art and refers to experiencing a mental process of disconnecting from one’s thoughts, feelings, memories, or sense of identity. In some cases, an individual undergoing a dissociative experience may feel like he or she is leaving his or her body.

“Dextrorphan” is a chemical compound of the morphinan class of chemical compounds. Dextrorphan may be abbreviated as “DXO.” Dextrorphan has the molecular formula of C17H23NO (CAS Registry Number 125-73-5) and the structure of:

As used therapeutically and in research, dextrorphan is typically in the form of a pharmaceutically acceptable salt. Accordingly, as used herein, the term “dextrorphan” is understood to refer to both the freebase and pharmaceutically acceptable salt forms of dextrorphan.

In some embodiments of the present method, the amount of orally or intranasally admini tered dextrorphan is sufficient to produce a blood concentration of dextrorphan or a cerebrospinal fluid concentration of dextrorphan in an individual sufficient to induce a dissociative experience from about 0.25 hours to about 4 hours after oral or intranasal administration of the dextrorphan, from about 0.5 hours to about 3.75 hours after oral or intranasal administration of the dextrorphan, from about 0.75 hours to about 3.5 hours after oral or intranasal administration of the dextrorphan, from about 1 hour to about 3.25 hours after oral or intranasal administration of the dextrorphan, from about 1.25 hours to about 3 hours after oral or intranasal administration of the dextrorphan, from about 1.5 hours to about 2.75 hours after oral or intranasal administration of the dextrorphan, from about 1.75 hours to about 2.5 hours after oral or intranasal administration of the dextrorphan, or from about 2 hours to about 2.25 hours after oral or intranasal administration of the dextrorphan. In some embodiments of the present method, the amount of orally or intranasally administered dextrorphan is sufficient to produce a blood concentration of dextrorphan or a cerebrospinal fluid concentration of dextrorphan in an individual sufficient to induce a dissociative experience about 2 hours after oral administration of the dextrorphan.

The term “concentration” refers to the amount of drug in a tissue, organ tissue, or bodily fluid, such as blood or cerebrospinal fluid, per unit area or volume of the tissue, organ tissue, or bodily fluid, such as blood or cerebrospinal fluid. Following administration of the drug, a sample, such as blood, cerebrospinal fluid, or organ tissue (such as liver tissue), can be obtained and analyzed for the concentration of the drug, and the time at which the Cmax, among other pharmacokinetic values, including but not limited to t_max, was reached can be calculated. The term “Cmax” refers to the maximum (peak) concentration a drug reaches in a tissue, organ tissue, or bodily fluid, such as blood or cerebrospinal fluid, of an individual after the individual has received a dose of the drug and before administration of a subsequent dose of the drug. The term “tmax” refers to the time it takes a drug to reach a maximum concentration in a tissue, organ tissue, or bodily fluid, such as blood or cerebrospinal fluid, of an individual after the individual has received a dose of the drug. In some embodiments, the concentration of the drug may be measured in the blood, the cerebrospinal fluid, or organ tissue, such as liver tissue.

In some embodiments, the dissociative experience induced by oral or intranasal administration of dextrorphan is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS). CADSS is a clinical instrument used to determine whether an individual has experienced dissociation. CADSS is a 23-item scored survey with each item divided into three categories: depersonalization, derealization, and amnesia. Each of the 23 questions are scored from 0 to 4 (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = “Severe”, 4 = “Extreme”) for a total of 92 points. An individual’s scores from each category is then summed to generate a score ranging from 0 to 92, with a higher score associated with a more dissociative experience. In some embodiments, an individual scores a CADSS value of 0 prior to administration of dextrorphan or any of the therapies described herein. In some embodiments, an individual scores a CADSS value greater than 0 prior to administration of dextrorphan or any of the therapies described herein. The CADSS can be measured prior to oral or intranasal administration of dextrorphan, or at any desired interval after oral or intranasal administration of dextrorphan, such as about 0.5 hour after oral or intranasal administration of dextrorphan, about 0.75 hour after oral or intranasal administration of dextrorphan, about 1 hour after oral or intranasal administration of dextrorphan, about 1.25 hours after oral or intranasal administration of dextrorphan, about 1.5 hours after oral or intranasal administration of dextrorphan, about 1.75 hours after oral or intranasal administration of dextrorphan, about 2 hours after oral or intranasal administration of dextrorphan, about 2.25 hours after oral or intranasal administration of dextrorphan, about 2.5 hours after oral or intranasal administration of dextrorphan, about 2.75 hours after oral or intranasal administration of dextrorphan, about 3 hours after oral or intranasal administration of dextrorphan, about 3.25 hours after oral or intranasal administration of dextrorphan, about 3.5 hours after oral or intranasal administration of dextrorphan, about 2 hours after oral or intranasal administration of dextrorphan, about 3 hours after oral or intranasal administration of dextrorphan, about 3.75 hours after oral or intranasal administration of dextrorphan and/or about 4 hours after oral or intranasal administration of dextrorphan.

Dextrorphan can be administered orally in any suitable form of delivery, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. Dextrorphan can be administered intranasally in any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension. A solid tablet can be produced from powdered dextrorphan with use of a tablet binder. A soft gel, aqueous solution, or liquid solution or suspension can be produced from powdered dextrorphan with use of an appropriate solvent, such as saline. In some embodiments, the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea, anxiety, vomiting, dizziness, urticaria, and/or histaminergic-release symptoms. The term “nausea” refers to a sensation or urge to vomit. Nausea may be accompanied with headaches, abdominal pain, and/or an overall unwell feeling. The term “histaminergic-release symptoms” refers to a physiological manifestation of or resembling an allergic reaction.

Another aspect of the present disclosure provides a method of treating depression in an individual comprising orally administering to an individual in need of treatment of depression, an amount (also referred to as a dose) of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours of administration. In one embodiment, the amount is from about 150 mg to about 600 mg. In some embodiments, the amount is from about 200 mg to about 500 mg. In some embodiments, the amount is from about 250 mg to about 300 mg. In some embodiments, the amount is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg.

Another aspect of the present disclosure provides a method of treating depression in an individual comprising administering, intranasally, to an individual in need of treatment of depression, an amount of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours after administration. In one embodiment, the amount is from about 50 mg to about 350 mg. In some embodiments, the amount is from about 100 mg to about 300 mg. In some embodiments, the amount is from about 150 mg to about 250 mg. In some embodiments, the amount is 100 mg, 200 mg, or 250 mg. In some embodiments, the amount is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg.

As used herein, the term “depression” refers to a class of mental health disorders characterized by depressive symptoms or loss of interest in activities, causing significant impairment in daily life. Symptoms and signs of depression include persistent sadness, anxiety, “empty” mood; feelings of hopelessness or pessimism; irritability; feelings of guilt, worthlessness, or helplessness; loss of interest or pleasure in hobbies and activities; decreased energy or fatigue; and difficulty concentrating, remembering, or making decisions, among many other symptoms.

In some embodiments, the amount of orally or intranasally administered dextrorphan is sufficient to produce a blood concentration of dextrorphan or a cerebrospinal fluid concentration of dextrorphan in the individual sufficient to induce the dissociative experience from about 0.25 hours to about 4 hours after oral or intranasal administration of the dextrorphan, from about 0.5 hours to about 3.75 hours after oral or intranasal administration of the dextrorphan, from about 0.75 hours to about 3.5 hours after oral or intranasal administration of the dextrorphan, from about 1 hour to about 3.25 hours after oral or intranasal administration of the dextrorphan, from about 1.25 hours to about 3 hours after oral or intranasal administration of the dextrorphan, from about 1.5 hours to about 2.75 hours after oral or intranasal administration of the dextrorphan, from about 1.75 hours to about 2.5 hours after oral or intranasal administration of the dextrorphan, or from about 2 hours to about 2.25 hours after oral or intranasal administration of the dextrorphan. In some embodiments of the present method, the amount of orally or intranasally administered dextrorphan is sufficient to produce a blood concentration of dextrorphan or a cerebrospinal fluid concentration of dextrorphan in an individual sufficient to induce a dissociative experience about 2 hours after oral or intranasal administration of the dextrorphan.

In some embodiments, the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish. In some embodiments, the individual is experiencing an episode of acute suicidal ideation. In some embodiments, the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

In some embodiments, the amount of orally or intranasally administered dextrorphan is sufficient to induce in the individual a dissociative experience. In some embodiments, the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS). In some embodiments, the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. In some embodiments, the intranasal administration of dextrorphan is carried out by intranasal administration of any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension. In some embodiments, the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea and histaminergic-release symptoms.

In some embodiments, the oral amount of dextrorphan from about 150mg to about 600mg is administered daily until the individual’s rating on a depression scale is reduced by at least 50%. In some embodiments, the oral amount of dextrorphan from about 150mg to about 600mg is administered intermittently until the individual’s rating on a depression scale is reduced by at least 50%. In some embodiments, the intranasal amount of dextrorphan from about 50mg to about 350mg is admini tered daily until the individual’s rating on a depression scale is reduced by at least 50%. In some embodiments, the intranasal amount of dextrorphan from about 50mg to about 350mg is administered intermittently until the individual’s rating on a depression scale is reduced by at least 50%. The term “intermittently” refers to every two days, every three days, every four days, every five days, and so on, until the individual’s rating on a depression scale is reduced by at least 50%. In some embodiments, the depression scale is selected from a group consisting of: Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Beck Depression Inventory, empirical observation by a clinician, or self-reported scale. The term “rating” refers to a score on a scale or questionnaire that is relevant to a particular disorder or experience.

The term “reduced score” refers to a score on a scale that is lower at a time point than a score on the same scale received at an earlier time point.

The term “Montgomery-Asberg Depression Rating Scale,” or “MADRS,” refers to a ten- item diagnostic questionnaire used to measure severity of depressive episodes with mood disorders (Montgomery, et al., The British Journal of Psychiatry, 1979).

The term “Hamilton Depression Rating Scale,” or “HDRS,” refers to a multiple item questionnaire used to provide an indication of depression in an individual (Hamilton, et al., Journal of Neurology, Neurosurgery, and Psychiatry, 1960). The term “Beck Depression Inventory,” or “BDI,” refers to a 21-item diagnostic questionnaire used to rate the severity of a respondent’s depression in the weeks preceding questionnaire completion (Beck, et al., Clin Psychol Rev, 1988).

The term “empirical observation by a clinician” refers to a process of evaluation performed by a clinician to determine severity of depression and depressive symptoms in an individual.

The term “self-reported scale” is one of a plurality of questionnaires that include multiple self-report items which measure major dimensions of depression experienced in a given amount of time.

In some embodiments, an individual who has experienced a dissociative experience induced within about 4 hours of oral or intranasal administration of dextrorphan is administered orally a subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg ( e.g .,

15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg); a dose of another, different drug or dmgs that is/are not dextrorphan; a non-drug therapy (e.g., psychotherapy); a combination of a subsequent dose of dextrorphan and a non-dmg therapy (e.g., psychotherapy; or a combination of a subsequent dose of dextrorphan and a dose of one or more additional, different drug(s) that is/are not dextrorphan to reduce (partially or completely) depression in the individual. The length of time (e.g., days, weeks, months, years) the subsequent dose of dextrorphan is administered alone, the subsequent dose of dextrorphan in combination with a non-drug therapy or the dose of another, different dmg(s) is administered, or the dose of another, different dmg(s) is administered without dextrorphan will vary, depending on the need of the individual being treated. In addition, the dose of dextrorphan and the dose of another, different drug(s) administered will vary, depending on the need of the individual being treated. For example, the length of time could be as short as one or two days or any sufficient time to maintain a reduction in or an absence of symptoms of depression. This could be, for example, at least 2 days. In some embodiments, from about 15 mg to about 100 mg (e.g., 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg) of dextrorphan is administered orally for at least seven days. In some embodiments, the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg (e.g., 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 85 mg). In some embodiments, the subsequent dose of dextrorphan is about 40 mg.

In some embodiments, the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish. In some embodiments, the individual might have depressive symptoms, but the individual has not been diagnosed as having depression. In some embodiments, the individual has been previously treated for depression by oral administration of an amount of dextrorphan from about 150mg to about 600mg. In some embodiments, the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS). In some embodiments, the subsequent dose of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

Another aspect of the present disclosure provides a method for treating depression in an individual who has experienced a dissociative experience induced by dextrorphan by administering orally at least one subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs that is/are not dextrorphan; a non drug therapy ( e.g psychotherapy); a combination of a subsequent dose of dextrorphan and a non-drug therapy (e.g., psychotherapy; or a combination of a subsequent dose of dextrorphan and a dose of one or more additional, different drug(s) that is/are not dextrorphan to reduce (partially or completely) depression in the individual. The length of time (e.g., days, weeks, months, years) the subsequent dose of dextrorphan is administered alone, the subsequent dose of dextrorphan in combination with the dose of another, different drug(s) is administered, or the dose of another, different drug(s) is administered without dextrorphan will vary, depending on the need of the individual being treated. In addition, the dose of dextrorphan and the dose of another, different drug(s) administered will vary, depending on the need of the individual being treated. For example, the length of time could be as short as one or two days or any sufficient time to maintain a reduction in or an absence of symptoms of depression. This could be, for example, at least 2 days. In some embodiments, from about 15 mg to about 100 mg of dextrorphan is administered orally for at least seven days. In some embodiments, the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg. In some embodiments, the subsequent dose of dextrorphan is about 40 mg.

In some embodiments, the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish. In some embodiments, the individual might have depressive symptoms, but the individual has not been diagnosed as having depression. In some embodiments, the individual has been previously treated for depression by oral administration of an amount of dextrorphan from about 150 mg to about 600 mg. In some embodiments, the individual has been previously treated for depression by intranasal administration of an amount of dextrorphan from about 50 mg to about 350 mg. In some embodiments, the amount does not induce in the individual a dissociative experience. In some embodiments, the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS). In some embodiments, the oral administration of dextrorphan is administered by any suitable method of oral administration, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. Another aspect of the present disclosure provides a pharmaceutical kit for treating depression in an individual, comprising at least one (one or more) oral dose of dextrorphan (dextrorphan suitable for oral administration) in an amount from about 150 mg to about 600 mg and a pharmaceutically acceptable excipient. In some embodiments, the at least one an individual who has experienced a dissociative experience induced by dextrorphan is administered orally at least one subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different dmg or drugs that is/are not dextrorphan; a non-drug therapy (e.g., psychotherapy); a combination of a subsequent dose of dextrorphan and a non-dmg therapy (e.g., psychotherapy; or a combination of a subsequent dose of dextrorphan and a dose of one or more additional, different drug(s) that is/are not dextrorphan to reduce (partially or completely) depression in the individual. The length of time (e.g., days, weeks, months, years) the subsequent dose of dextrorphan is administered alone, the subsequent dose of dextrorphan in combination with the dose of another, different drug(s) is administered, or the dose of another, different dmg(s) is administered without dextrorphan will vary, depending on the need of the individual being treated. In addition, the dose of dextrorphan and the dose of another, different drug(s) admini tered will vary, depending on the need of the individual being treated. For example, the length of time could be as short as one or two days or any sufficient time to maintain a reduction in or an absence of symptoms of depression. This could be, for example, at least 2 days. In some embodiments, from about 15 mg to about 100 mg of dextrorphan is administered orally for at least seven days. In some embodiments, the subsequent dose of dextrorphan is an amount from about 30mg to about 85mg. In some embodiments, the subsequent dose of dextrorphan is about 40mg.

Another aspect of the present disclosure provides a pharmaceutical kit for treating depression in an individual who has been previously treated for depression by oral administration of an amount of dextrorphan sufficient to induce a dissociative experience, comprising a package containing single oral dosage forms of an amount of dextrorphan from about 15 mg to about 600 mg in each single dosage form, wherein each dosage form is separately contained in a different compartment in the package and instmctions for oral administration not more than once daily. In some embodiments, each oral dosage form of dextrorphan is a single dosage in any form suitable for oral administration, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. In some embodiments, the single oral dosage forms of an amount of dextrorphan are referred to (labeled) as initial dose or subsequent dose. In some embodiments, the initial dose is an amount of dextrorphan from about 150 mg to about 600 mg. In some embodiments, the amount of dextrorphan in the initial dose is sufficient to induce a dissociative experience in-an individual within 4 hours after administration· In some embodiments, the instructions state that the initial dose should be administered intermittently until an individual’s score on a depression rating scale is reduced by at least 50%. In some embodiments, the instructions state that the initial dose should be administered intermittently until an individual’s score on a depression rating scale is improved by at least 50%. In some embodiments, the subsequent dose is an amount of dextrorphan from about 15 mg to about 100 mg. The amount of dextrorphan in the subsequent dose is not sufficient to induce a dissociative experience in an individual. In some embodiments, the instructions state that the- subsequent dose should be admini tered daily until the individual does not experience depressive symptoms in the absence of the subsequent dose. Dextrorphan Metabolism and Bioavailability

“Dextrorphan” is a chemical compound of the morphinan class of chemical compounds. In some embodiments, dextrorphan is abbreviated as “DXO.” In some embodiments, dextrorphan is abbreviated as “DO.” Dextrorphan has the molecular formula of C17H23NO (CAS Registry Number 125-73-5). Dextrorphan is the dextrorotatory-stereoisomer of racemorphan with the levo-half being levorphanol, as well as a desmethyl metabolite of dextromethorphan (“DXM”). Dextromethorphan is a widely used antitussive drug that is metabolized by cytochrome P450 2D6 (CYP2D6) in the liver. Dextrorphan is produced in vivo by the O-demethyl at ion of dextromethorphan by CYP2D6. Dextrorphan produced by the metabolism of dextromethorphan may contribute to the psychoactive effects experienced by those who abuse dextromethorphan. This is further supported by evidence showing that dextrorphan is an antagonist of N-methyl-D- aspartate (NMD A) receptors. Dextrorphan has a half-life of 6-12 hours and is finally metabolized in the liver by CYP3A4 and excreted in urine. Aspects of the present disclosure relate to the use of dextrorphan as a rapid-acting antidepressant. In some embodiments, dextrorphan may act as a rapid-acting antidepressant due to its psychoactive effects. Subjects who ingest dextrorphan or inhale dextrorphan may undergo a dissociative experience, including hallucinations and perceptual alterations. Because dextromethorphan is first metabolized in the liver to produce dextrorphan, the metabolism of dextromethorphan results in unpredictable onset of effects, therefore dextromethorphan is not an ideal candidate as a rapid-acting antidepressant. Aspects of the present disclosure relate to the pharmacokinetic benefits of treatment with dextrorphan alone. Because dextrorphan does not require first-pass metabolism in the liver, it becomes bioavailable at a faster rate compared to dextromethorphan .

Clinician-Administered Dissociative States Scale (CADSS)

Aspects of the present disclosure relate to the use of dextrorphan to induce psychoactive effects in a subject by acting as a NMDA receptor antagonist. NMDA receptor antagonism has been shown to reduce glutamatergic excitotoxicity, which may contribute to the psychoactive effects of dextrorphan. Aspects of the present disclosure relate to the idea that NMDA receptor antagonism is associated with induction of a dissociative experience in a subject and consequent antidepressant effects (Prasko, J., Grambal, A., Kasalova, P., Kamardova, D., Ociskova, M., Holubova, M., Vrbova, K., Sigmundova, Z., Latalova, K., Slepecky, M., & Zatkova, M. (2016). “Impact of dissociation on treatment of depressive and anxiety spectrum disorders with and without personality disorders.” Neuropsychiatric disease and treatment, 12, 2659-2676; Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016). “Ketamine: NMDA Receptors and Beyond”. The Journal of Neuroscience, 36(44), 11158-11164). The term “dissociative experience,” as used herein, refers to an experience of feeling disconnected from thoughts, feelings, memories, and/or surroundings. The inventors of the present disclosure made the surprising discovery that oral and nasal administration of dextrorphan indeed induces a dissociative experience in a subject and has the potential to act as a rapid-acting antidepressant.

The Clinician- Administered Dissociative States Scale (CADSS) is a multi-question survey or questionnaire (CADSS questionnaire) designed as an instrument for the measurement of present-state dissociative symptoms or of a dissociative experience (Bremner, et al. J. Trauma Stress (1998)). The CADSS survey includes questions related to distortions in perception of self, distortions in perception of the passing of time, event recall, ability to feel, ability to concentrate, and others. In some embodiments, the survey includes 23 questions, each scored on a scale from 0-4. In some embodiments, survey results are analyzed to generate a single score on a 92 -point scale (e.g., 0-92) that is associated with an individual’s level of dissociation. In some embodiments, a score between 1-5, inclusive, on the 92-point scale is considered to be an optimal level of dissociation. In some embodiments, a score of 1, 2, 3, 4, or 5, on the 92-point scale is considered to be an optimal level of dissociation. A score greater than 5 (e.g., 6, 7, 8, 9, 10, or more) on the 92-point scale is considered to be a sub-optimal level of dissociation. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score between 1-5. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 1, 2, 3, 4, or 5. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 1. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 2. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 3. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 4. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of 5. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of less than 6. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6.

In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 0.5-4 hours. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 1-3.5 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 1.5-3 hours after administration of dextrorphan after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 2-2.5 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 0.5-4 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 4 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 3 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 2 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 1 hours after administration of dextrorphan. In some embodiments, a therapeutically effective dose of dextrorphan results in a CADSS score of greater than 0 and less than 6 within 0.5 hours after administration of dextrorphan.

In some embodiments, dextrorphan is administered at a maintenance dose following an initial dose or a loading dose. In some embodiments, dextrorphan administered at a maintenance dose is administered at a therapeutically effective dose that results in a CADSS score of 0.

As described herein and will be appreciated by a person having ordinary skill in the art, a dissociative experience is associated with improved outcomes related to mental health disorders, such as depression. Without wishing to be bound by theory, a dissociative experience induced by antagonism of NMDA receptors in an individual’ s brain is likely to result in improved outcomes related to a mental health disorder, such as a depressive disorder. As described herein, oral or intranasal (nasal) administration of dextrorphan induces a dissociative experience in an individual, as measured by a CADSS score of greater than 1 and less than 6, which is therapeutically effective in treating a mental health disorder, such as a depressive disorder.

Depression

Features Depression is characterized by depressed mood and/or a markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts. A variety of somatic symptoms may also be present. Though depressive feelings are common, depressive disorder is diagnosed only when the symptoms reach a threshold and last at least two weeks. Depression can vary in severity from mild to very severe. It is most often episodic but can be recurrent or chronic. Some individuals may have only a single episode, with a full return to premorbid function. However, more than 50 percent of those who initially suffer a single major depressive episode eventually develop another.

Types of Depressive Disorders

Several types of depressive disorders are well-characterized and will be known by those having ordinary skill in the art. Major depression (or major depressive disorder) is characterized by peak episodes of extreme depression. During a peak episode, an individual may suffer from depressed mood, and markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts. Symptoms last for at least two weeks and cause significant distress or impairment in important areas of functioning.

Dysthymia is characterized by depressed mood for at least 2 years as well as other symptoms like poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions and feelings of hopelessness.

As is recognized in the field of psychiatric arts, depression may also comprise, and/or may also manifest itself in a variety of forms, including but not limited to, seasonal affective disorder, diurnal mood variations, or depression associated with menopause. Diagnostic criteria for dysthymia and major depression, as well as for seasonal affective disorder, diurnal mood variations and depression associated with menopause, are more fully explained in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM IV) published by the American Psychiatric Association or by the ICD (ICD-10: International Statistical Classification of Diseases and Related Health Problems (10th Revision) or any other psychiatric classification system. Depression with seasonal affective pattern or seasonal affective disorder (hereinafter referred to as “SAD”) is also known as cabin fever, evening blues, and sun deprivation syndrome. The terms “seasonal affective disorder” or “seasonal pattern specifier” are defined in the DSM-IV as a specifier or adjective that more precisely characterize feature associated with depression. A particular feature of SAD is the regular occurrence of depression in winter.

Most of the patients with SAD are characterized by an atypical type of depression in the winter which is associated with mood reactivity (mood brightens in response to actual or potential positive events) as well as weight gain or increase in appetite, hypersomnia, leaden paralysis (heavy, leaden feelings in arms or legs), long-standing pattern of interpersonal rejection sensitivity.

In some embodiments, TRD is depression that is non-responsive to more than one antidepressant treatment titrated to their maximum effective and tolerated doses. In some embodiments, treatment resistant depression (TRD) is depression that is non-responsive to more than two antidepressant treatments titrated to their maximum effective and tolerated doses. In some embodiments, TRD is depression that is characterized as an inadequate response in an individual to one or more treatments for depression.

Diagnosis

The diagnosis of depression follows a clinical evaluation. The two most recognized sets of diagnostic criteria for major depressive disorder and other depressive, or mood disorders, are outlined in the DSM, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM IV) published by the American Psychiatric Association and the ICD (ICD-10: International Statistical Classification of Diseases and Related Health Problems- 10th Revision, published periodically by the World Health Organization) or any other psychiatric classification system.

Prevalence

Depression is among the most disabling of all medical disorders with a lifetime prevalence of approximately 17%. It frequently appears early in life, can run a chronic course, and adversely affect the prognosis of other medical illnesses, such as coronary vascular disease, diabetes, and osteoporosis. Depression is more common in women than in men. The point prevalence of unipolar depressive episodes is estimated to be 1.9% for men and 3.2% for women, and 5.8% of men and 9.5% of women will experience a depressive episode in a 12-month period. These prevalence figures vary across populations and may be higher in some populations. A World Health Organization study has reported that depression is the leading global cause of years of life lived with disability and the fourth leading cause of disability-adjusted life-years. Disability-adjusted life-years refers to the reduction in an individual's productive life and is a measure that takes into account premature mortality.

Treatment

The treatment of depression was revolutionized about a half-century ago by the serendipitous discovery of monoamine oxidase inhibitors and tricyclic antidepressants. Since then, the availability of a host of newer medications with better side effect profiles has greatly increased our ability to safely treat a significant percentage of patients. However, the newer medications are largely drugs that merely augment or otherwise potentiate the effects of the existing drugs by exerting their primary biochemical effects by increasing levels of monoamines in the brain.

Current medications for the treatment of depression take weeks to months to achieve their full effects and in the meantime, patients continue to suffer from their symptoms and continue to be at risk of self-harm as well as harm to their personal and professional lives. Indeed, the lag period of onset of action of several weeks of traditional antidepressants is recognized as a major limitation, resulting in considerable morbidity and high risk of suicidal behavior especially in the first 9 days of starting antidepressants. Pharmacological strategies that have rapid onset of antidepressant effects within hours or a few days and that are sustained would therefore have an enormous impact on public health.

Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity and high risk of suicidal behavior and ideation. Recently, there has been an attempt to overcome the deficits of conventional therapies for depressive disorders. Ketamine and its enantiomers, for example, have received increasing popularity as potential rapid-acting antidepressants; however, ketamine is a tightly controlled substance, it induces levels of dissociation far beyond the desired range for therapy, and it exhibits poor bioavailability when administered orally (Carboni, E., Carta, A.R., & Novelli, A. (2021). “Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?” Frontiers in Neuroscience, 15). Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days, that are widely accessible, and that are sustained would have an enormous impact on patient care. For example, ketamine is classified by the United States Drug Enforcement Administration as a Schedule III controlled substance, making it difficult to obtain, while dextrorphan is unscheduled. The present disclosure is directed to address this unmet need in psychiatric medicine.

Therapeutic Compositions and Method of Use

The present disclosure provides, in some embodiments, therapeutic compositions comprising the dextrorphan composition described herein. In some embodiments, the compositions further comprise a pharmaceutically-acceptable excipient. In some embodiments, dextrorphan is administered in the form of a pharmaceutically-acceptable salt.

As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci - alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Cl-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

Such compositions may be admini tered to a subject, such as a human subject, using any suitable route of administration. Suitable routes of administration include, for example, oral or intranasal (nasal). Other examples include parenteral routes such as intravenous, intrathecal, parenchymal, or intraventricular routes.

In some embodiments, a subject is a human subject. The subject may have a mental health disorder, such as depression. Depression includes major depressive disorder, treatment- resistant disorder, and other forms of depression described herein. Depression may be diagnosed using any one of the depression measurement scales described herein.

In some embodiments, any of the doses of dextrorphan or another drug described herein may be administered in combination with dextromethorphan. In some embodiments, any of the doses of dextrorphan or another drug described herein may be administered in combination with a non-drug therapy. In some embodiments, a non-drug therapy refers to psychotherapy, cognitive-behavioral therapy, meditation, breathing exercises, mindfulness exercises, hand holding, or another non-drug therapeutic intervention.

The compositions may be administered to a subject in a therapeutically effective amount. The term “ “therapeutically effective amount” refers to the amount of dextrorphan required to confer therapeutic effect on a subject, either alone or in combination with at least one other active agent. Effective amounts vary, as recognized by those skilled in the art, depending on the route of administration, excipient usage, and co-usage with other active agents. The quantity to be administered depends on the subject to be treated, including, for example, the strength of an individual’s immune system, concomitant medications use, or genetic predispositions. The dosage of the preparations disclosed herein may depend on the route of administration and varies according to the size of the subject.

A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

In some embodiments, dextrorphan is administered with an additional active agent. In some embodiments, the additional active agent is administered before dextrorphan is admini tered. In some embodiments, the additional active agent is administered at the same time dextrorphan is administered. In some embodiments, the additional active agent is administered after dextrorphan is administered. In some embodiments, the additional active agent is dextromethorphan. In some embodiments, dextrorphan is administered with an adjunctive therapy. In some embodiments, dextrorphan is administered with a selective or nonselective serotonin reuptake inhibitor such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, or others, wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a selective or nonselective norepinephrine reuptake inhibitor such as bupropion, desipramine, nortriptyline, protriptyline, tapentadol, teniloxazine, atomoxetine, reboxetine, viloxazine, venlafaxine, or others, wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a selective or nonselective dopamine reuptake inhibitor such as methylphenidate, dextroamphetamine, methamphetamine, lisdexamfetamine, modafinil, or others, wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with an neuroleptic such as haloperidol, clozapine, amisulpride, lurasidone, risperidone, aripiprazole, brexpiprazole, asenapine, olanzapine, quetiapine, pimavanserin, or others, wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a monoamine oxidase inhibitor such as phenelzine, rasagiline, selegiline, hydracarbazine, tranylcypromine, isocarboxazid, hydracarbazine, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a NMDA receptor antagonist such as memantine, ketamine, esketamine, arketamine, rapastinel, dextromethorphan, nitrous oxide, phencyclidine, xenon, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with an opioid receptor ligand such as naltrexone, naloxone, buprenorphine, hydrocodone, etorphine, oxycodone, fentanyl, carfentanyl, remifentanil, methadone, ethorphine, levorphanol, levomethorphan, racemethorphan, mitragynine, tramadol, naloxone, nalmefene, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a GABAergic drug such as diazepam, flurazepam, lorazepam, temazepam, midazolam, alprazolam, primidone, phenobarbital, ethanol, sodium thiopental, 1 ,4 butanediol secobarbital, butabarbital, amobarbital, brexanolone, allopregnanolone, phenibut, gamma hydroxybutyric acid, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with an antiepileptic, such as lithium, valproate, lamotrigine, topiramate, levetiracetam, gabapentin, pregabalin, carbamazepine, oxcarbazepine, zonisamide, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with a cholinergic drug (ligand or modulator) such as atropine, benztropine, cyclopentolate, choline, citicholine, L-alpha glycerylphosphorylcholine, centrophenoxine, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated. In some embodiments, dextrorphan is administered with an immunological intervention such as an mTOR inhibitor (rapamycin and rapalogs), monoclonal antibody, nonsteroidal anti inflammatory drug, corticosteroid, probiotic, prebiotic, or fecal microbiota transplant. In some embodiments, dextrorphan is administered with an electromagnetic intervention such transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, or others wherein the adjunctive therapy may be initiated with the first dose of dextrorphan, or later initiated and titrated.

In some embodiments, dextrorphan is administered with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered before dextrorphan is administered. In some embodiments, the additional therapeutic agent is administered at the same time dextrorphan is administered. In some embodiments, the additional therapeutic agent is administered after dextrorphan is administered. In some embodiments, the additional therapeutic agent is: dextromethorphan; a selective or nonselective serotonin reuptake inhibitor such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, or others; a selective or nonselective norepinephrine reuptake inhibitor such as bupropion, desipramine, nortriptyline, protriptyline, tapentadol, teniloxazine, atomoxetine, reboxetine, viloxazine, venlafaxine, or others; a selective or nonselective dopamine reuptake inhibitor such as methylphenidate, dextroamphetamine, methamphetamine, lisdexamfetamine, modafinil, or others; a neuroleptic such as haloperidol, clozapine, amisulpride, lurasidone, risperidone, aripiprazole, brexpiprazole, asenapine, olanzapine, quetiapine, pimavanserin, or others; a monoamine oxidase inhibitor such as phenelzine, rasagiline, selegiline, hydracarbazine, tranylcypromine, isocarboxazid, hydracarbazine, or others; a NMDA receptor antagonist such as memantine, ketamine, esketamine, arketamine, rapastinel, dextromethorphan, nitrous oxide, phencyclidine, xenon, or others; an opioid receptor ligand such as naltrexone, naloxone, buprenorphine, hydrocodone, etorphine, oxycodone, fentanyl, carfentanyl, remifentanil, methadone, ethorphine, levorphanol, levomethorphan, racemethorphan, mitragynine, tramadol, naloxone, nalmefene, or others; a GABAergic drug such as diazepam, flurazepam, lorazepam, temazepam, midazolam, alprazolam, primidone, phenobarbital, ethanol, sodium thiopental, 1 ,4 butanediol secobarbital, butabarbital, amobarbital, brexanolone, allopregnanolone, phenibut, gamma hydroxybutyric acid, or others; an antiepileptic, such as lithium, valproate, lamotrigine, topiramate, levetiracetam, gabapentin, pregabalin, carbamazepine, oxcarbazepine, zonisamide, or others; a cholinergic drug (ligand or modulator) such as atropine, benztropine, cyclopentolate, choline, citicholine, L-alpha glycerylphosphorylcholine, centrophenoxine, or others; an immunological intervention such as an mTOR inhibitor (rapamycin and rapalogs), monoclonal antibody, nonsteroidal anti inflammatory drug, corticosteroid, probiotic, prebiotic, or fecal microbiota transplant; an electromagnetic intervention such transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, or others.

In some embodiments, dextrorphan is administered with a non-drug therapy. In some embodiments, the non-drug therapy is administered before dextrorphan is administered. In some embodiments, the non-drug therapy is administered at the same time dextrorphan is admini tered. In some embodiments, the non-drug therapy is administered after dextrorphan is administered. In some embodiments, the non-drug therapy is psychotherapy, breathing exercises, hand holding or affective touch, exposure to augmented reality, rapport building, post-dose debriefing, vagal nerve stimulation, acupuncture, or support of a trained individual or “trip sitter” who guides and supports the subject through treatment.

It is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited in the present application are incorporated by reference for the purposes or subject matter referenced in this disclosure.

EXAMPLES

In order that the invention described in the present application may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the systems and methods provided in this disclosure and are not to be construed in any way as limiting their scope.

Example 1: Pharmacokinetic Analysis of Dextrorphan in Human Subjects

To determine the bioavailability of dextrorphan following oral and intranasal administration, dextrorphan in its salt (dextrorphan tartrate) state was administered to human subjects either orally as a gelatin capsule or intranasally as a nasal spray comprising dextrorphan in a saline solution. Oral dextrorphan was administered to two subjects at 150 mg. Intranasal dextrorphan was administered to one subject as three separate nasal sprays at 20 mg of dextrorphan per spray, resulting in a total dose of 60 mg of dextrorphan. Following either oral or nasal administration, blood serum was collected from each subject immediately after administration, 40 minutes after administration, 60 minutes after administration, 120 minutes after administration, and 240 minutes after administration. Blood serum was collected via intravenous (I.V.) cannulation. Collected blood serum was analyzed by liquid chromatography-mass spectrometry (LC-MS) to determine the blood serum concentration in each subject at each timepoint. Table 1 and FIG. 1 show the serum concentration for each subject at each timepoint.

Table 1. Blood Serum Concentration for Each Subject at Each Timepoint

The first 150 mg oral dose of dextrorphan reached a maximum blood serum concentration of 50.2 ng/mL 60 minutes after administration. The second 150 mg oral dose of dextrorphan reached a maximum blood serum concentration of 41.1 ng/mL 60 minutes after administration. The 60 mg nasal dose of dextrorphan reached a maximum blood serum concentration of 60.4 ng/mL 40 minutes after administration. It is possible that the nasal dose reached a maximum concentration earlier than 40 minutes after administration.

These data suggest that oral and intranasal administration of dextrorphan in its salt (dextrorphan tartrate) state reach a maximum blood serum concentration within 60 minutes of administration. Example 2: Dissociative Effects of Dextrorphan in Human Subjects

To determine whether oral and intranasal administration of dextrorphan result in a dissociative experience in human subjects, dextrorphan in its salt (dextrorphan tartrate) state was administered to subjects either orally as a gelatin capsule or intranasally as a nasal spray and dissociation was measured using the Clinician- Administered Dissociative States Scale (CADSS). Oral dextrorphan was administered to one subject at 50 mg, two subjects at 150 mg, one subject at 300 mg, one subject at 600 mg, and one subject at 750 mg. Intranasal dextrorphan was administered to one subject as three separate nasal sprays at 20 mg of dextrorphan per spray, resulting in a total dose of 60 mg of dextrorphan.

Following either oral or intranasal administration, subjects were assessed for dissociation by responding to the CADSS questionnaire immediately after administration, 40 minutes after administration, 60 minutes after administration, 120 minutes after administration, and 240 minutes after administration. Table 2 and FIG. 2 show the CADSS scores for each subject at each timepoint.

Table 2. CADSS Scores for Each Subject at Each Timepoint

The 50 mg oral dose of dextrorphan did not induce a dissociative experience as measured by the CADSS questionnaire. The first 150 mg oral dose of dextrorphan reached a maximum CADSS score of 2, 60 minutes after administration. The second 150 mg oral dose of dextrorphan reached a maximum CADSS score of 3, 120 minutes after administration. The 300 mg oral dose of dextrorphan reached a maximum CADSS score of 3, 60 minutes after administration. The 600 mg oral dose of dextrorphan reached a maximum CADSS score of 5, 60 minutes after administration. The 750 mg oral dose of dextrorphan reached a maximum CADSS score of 9, 60 minutes after administration. The 60 mg intranasal dose of dextrorphan reached a maximum CADSS score of 5, 40 minutes after administration.

These data suggest that oral and intranasal administration of dextrorphan in its salt (dextrorphan tartrate) state reach a maximum CADSS score within an average of 60 minutes of administration. Importantly, a CADSS score between 1 and 5 is considered to be an optimal level of dissociation. A CADSS score of 9, as seen for the 750 mg oral dose of dextrorphan, is considered to be a sub-optimal result of dextrorphan administration. The subject who reported a CADSS score of 9 reported great bodily discomfort and showed signs of urticaria. A CADSS score of greater than 5 (e.g., 9) indicates that the subject is severely impaired, which is associated with nausea, vomiting, anxiety, loss of consciousness, and great bodily discomfort, side-effects that the inventors of the present disclosure seek to avoid.

Example 3: Dissociative Effects of a Dextrorphan/Dextromethorphan Combination Therapy in Human Subjects Without wishing to be bound by any theory, the inventors of the present disclosure hypothesized that a combination therapy comprising dextrorphan, having a fast onset and metabolic elimination, and dextromethorphan, having a slow onset and metabolic elimination would prolong the dissociative experience without increasing the intensity of dissociation.

To test this hypothesis, 150 mg of dextrorphan tartrate delivered as a powder in a gelatin capsule and 60 mg of dextromethorphan hydrochloride delivered as two 30 mg tablets were admini tered orally to one healthy subject. Within 30 minutes of administration, the subject reported an onset of dissociative symptoms consistent with a therapeutic dose, which sustained in intensity for 2 hours, after which symptoms of dissociation subsided. The subject reported a feeling of lightheadedness and being distanced from the world and their own emotions. EMBODIMENTS

1. A method of inducing a dissociative experience in an individual, comprising orally administering to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration. 2. The method of Embodiment 1, wherein the amount is from about 150 mg to about 600 mg.

3. The method of Embodiment 1, wherein the amount is from about 200 mg to about 500 mg.

4. The method of Embodiment 1, wherein the amount is from about 250 mg to about 300 mg.

5. The method of Embodiment 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 4 hours after oral administration of dextrorphan.

6. The method of Embodiment 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

7. The method of Embodiment 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

8. The method of Embodiment 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan. 9. The method of Embodiment 1, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS).

10. The method of any one of Embodiments 1-9, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. 11. A method of inducing a dissociative experience in an individual, comprising intranasal administration to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration.

12. The method of Embodiment 11, wherein the amount is from about 50 mg to about 350 mg. 13. The method of Embodiment 11, wherein the amount is from about 100 mg to about 300 mg.

14. The method of Embodiment 11, wherein the amount is from about 150 mg to about 250 mg.

15. The method of Embodiment 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 4 hours after oral administration of dextrorphan. 16. The method of Embodiment 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

17. The method of Embodiment 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

18. The method of Embodiment 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan.

19. The method of Embodiment 11, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered

Dissociative States Scale (CADSS).

20. The method of any one of Embodiments 11-19, wherein the intranasal administration of dextrorphan is carried out by intranasal administration of any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension. 21. The method of any one of Embodiments 11-20, wherein the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea and histaminergic-release symptoms.

22. A method of treating depression in an individual, comprising orally administering, to an individual in need of treatment of depression, an amount of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours after administration.

23. The method of Embodiment 22, wherein the amount is from about 150 mg to about 600 mg.

24. The method of Embodiment 22, wherein the amount is from about 200 mg to about 500 mg.

25. The method of Embodiment 22, wherein the amount is from about 250 mg to about 300 mg. 26. The method of Embodiment 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual between 0.5 hours and 4 hours after oral administration of dextrorphan.

27. The method of Embodiment 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

28. The method of Embodiment 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

29. The method of Embodiment 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan.

30. The method of any one of Embodiments 22-29, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

31. The method of any one of Embodiments 22-29, wherein the individual is experiencing an episode of acute suicidal ideation. 32. The method of any one of Embodiments 22-29, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having depression.

33. The method of any one of Embodiments 22-29, wherein the amount is sufficient to induce in the individual a dissociative experience. 34. The method of Embodiment 33, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS).

35. The method of Embodiment 22, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

36. The method of any one of Embodiments 22-29, wherein the amount of dextrorphan from about 150 mg to about 600 mg is administered daily until the individual’s rating on a depression scale is reduced by at least 50%.

37. The method of Embodiment 36, wherein the depression scale is selected from a group consisting of: Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Beck Depression Inventory, empirical observation by a clinician, or self-reported scale.

38. The method of any one of Embodiments 22-37, wherein the individual has previously experienced the dissociative experience induced by dextrorphan and is subsequently admini tered orally a subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different drug(s) to reduce depression in the individual.

39. The method of Embodiment 38, wherein the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg. 40. The method of Embodiment 38, wherein the subsequent dose of dextrorphan is about 40 mg.

41. The method of any one of Embodiments 38-40, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

42. The method of any one of Embodiments 38-40, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder. 43. The method of any one of Embodiments 38-40, wherein the individual has been previously treated for a depressive disorder by oral administration of an amount of dextrorphan from about 150 mg to about 600 mg.

44. The method of any one of Embodiments 38-40, wherein the subsequent dose of dextrorphan does not induce in the individual a dissociative experience. 45. The method of Embodiment 44, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

46. The method of any one of Embodiments 38-40, wherein the subsequent dose of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

47. A method of treating depression in an individual, comprising administering, intranasally, to an individual in need of treatment of depression, an amount of dextrorphan sufficient to induce a dissociative experience in the individual within 4 hours after administration.

48. The method of Embodiment 47, wherein the amount is from about 50 mg to about 350 mg. 49. The method of Embodiment 47, wherein the amount is from about 100 mg to about 300 mg.

50. The method of Embodiment 47, wherein the amount is from about 150 mg to about 250 mg.

51. The method of Embodiment 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual between 0.5 hours and 4 hours after intranasal administration of dextrorphan. 52. The method of Embodiment 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 2 hours after intranasal administration of dextrorphan. 53. The method of Embodiment 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after intranasal administration of dextrorphan.

54. The method of Embodiment 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after intranasal administration of dextrorphan.

55. The method of any one of Embodiments 47-54, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

56. The method of any one of Embodiments 47-54, wherein the individual is experiencing an episode of acute suicidal ideation.

57. The method of any one of Embodiments 47-54, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder. 58. The method of any one of Embodiments 47-54, wherein the amount is sufficient to induce in the individual a dissociative experience.

59. The method of Embodiment 58, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS). 60. The method of Embodiment 47, wherein the intranasal administration of dextrorphan is carried out by intranasal administration of any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension.

61. The method of any one of Embodiments 47-60, wherein the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea and histaminergic-release symptoms. 62. The method of any one of Embodiments 47-54, wherein the amount of dextrorphan from about 50 mg to about 350 mg is administered daily until the individual’s rating on a depression scale is reduced by at least 50%.

63. The method of Embodiment 62, wherein the depression scale is selected from a group consisting of: Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Beck Depression Inventory, empirical observation by a clinician, or self-reported scale.

64. The method of any one of Embodiments 47-63, wherein the individual has previously experienced the dissociative experience induced by dextrorphan and is subsequently administered orally a subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different drug(s) to reduce depression in the individual.

65. The method of Embodiment 64, wherein the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg. 66. The method of Embodiment 64, wherein the subsequent dose of dextrorphan is about 40 mg.

67. The method of any one of Embodiments 64-66, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish. 68. The method of any one of Embodiments 64-66, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

69. The method of any one of Embodiments 64-66, wherein the individual has been previously treated for a depressive disorder by intranasal administration of an amount of dextrorphan from about 50 mg to about 350 mg. 70. The method of any one of Embodiments 64-66, wherein the subsequent dose of dextrorphan does not induce in the individual a dissociative experience. 71. The method of Embodiment 70, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

72. The method of any one of Embodiments 64-66, wherein the subsequent dose of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

73. A method for treating depression in an individual, comprising orally administering a subsequent dose of dextrorphan to the individual, wherein the individual has previously experienced a dissociative experience induced by dextrorphan and is administered orally the subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different drug(s) to reduce depression in the individual.

74. The method of Embodiment 73, wherein the amount is from about 30 mg to about 85 mg.

75. The method of Embodiment 73, wherein the amount is about 40 mg. 76. The method of any one of Embodiments 73-75, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

77. The method of any one of Embodiments 73-75, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder .

78. The method of any one of Embodiments 73-75, wherein the individual has been previously treated for depression by oral administration of an amount of dextrorphan from about 150 mg to about 600 mg.

79. The method of any one of Embodiments 73-75, wherein the individual has been previously treated for depression by intranasal administration of an amount of dextrorphan from about 50 mg to about 350 mg.

80. The method of any one of Embodiments 73-75, wherein the amount does not induce in the individual a dissociative experience. 81. The method of Embodiment 80, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

82. The method of any one of Embodiments 73-75, wherein the oral administration of dextrorphan is administered by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

83. A pharmaceutical composition for treating depression in an individual, comprising a single oral dose of dextrorphan in an amount from about 150 mg to about 600 mg and a pharmaceutically acceptable excipient.

84. The pharmaceutical composition of Embodiment 83, wherein the single oral dose of dextrorphan is a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

85. A pharmaceutical composition for treating depression in an individual, comprising a single intranasal dose of dextrorphan in an amount from about 50 mg to about 350 mg and a pharmaceutically acceptable excipient.

86. The pharmaceutical composition of Embodiment 85, wherein the single intranasal dose of dextrorphan is an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension. 87. A pharmaceutical kit for treating depression in an individual, comprising a package containing single oral dosage forms of an amount of dextrorphan from about 15 mg to about 600 mg in each single dosage form, wherein each dosage form is separately contained in a different compartment in the package and instructions for oral administration indicate not more than one dose daily. 88. The pharmaceutical kit of Embodiment 87, wherein each oral dosage form of dextrorphan is a single dosage suitable for oral administration, such as a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension. 89. The pharmaceutical kit of Embodiment 87, wherein single oral dosage forms of an amount of dextrorphan are labeled initial dose or subsequent dose.

90. The pharmaceutical kit of Embodiment 89, wherein the initial dose is an amount of dextrorphan from about 150 mg to about 600 mg. 91. The pharmaceutical kit of Embodiment 90, wherein the amount of dextrorphan in the initial dose is sufficient to induce a dissociative experience in an individual within 4 hours of administration.

92. The pharmaceutical kit of any one of Embodiments 87-91, wherein the instructions state that the initial dose should be administered intermittently until an individual’s score on a depression rating scale is reduced by at least 50%.

93. The pharmaceutical kit of Embodiment 89, wherein the subsequent dose is an amount of dextrorphan from about 15 mg to about 100 mg.

94. The pharmaceutical kit of Embodiment 93, wherein the amount of dextrorphan in the subsequent dose is not sufficient to induce a dissociative experience in an individual. 95. The pharmaceutical kit of any one of Embodiments 87-94, wherein the instructions state that the subsequent dose should be administered daily until an individual does not experience depressive symptoms in the absence of the dose.

96. A method of inducing a dissociative experience in an individual as measured by a Clinician- Administered Dissociative States Scale (CADSS) score, comprising orally or nasally administering to the individual an amount of dextrorphan such that an individual reports a CADSS score of 1-5 within 1.5 hours after administration.

97. The method of Embodiment 96, wherein the amount is from about 150 mg to about 600 mg.

98. The method of Embodiment 96, wherein the amount is from about 200 mg to about 500 mg.

99. The method of Embodiment 96, wherein the amount is from about 250 mg to about 300 mg. 100. The method of Embodiment 96, wherein the individual reports a CADSS score of 1 within

1.5 hours after administration_· 101. The method of Embodiment 96, wherein the individual reports a CADSS score of 2 within

1.5 hours after administration.

102. The method of Embodiment 96, wherein the individual reports a CADSS score of 3 within

1.5 hours after administration. 103. The method of Embodiment 96, wherein the individual reports a CADSS score of 4 within

1.5 hours after administration.

104. The method of Embodiment 96, wherein the individual reports a CADSS score of 5 within

1.5 hours after administration.

105. The method of Embodiment 96, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience as measured by a CADSS score between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

106. The method of any one of Embodiments 96-105, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

107. The method of any one of Embodiments 96-105, wherein the nasal administration of dextrorphan is carried out by intranasal administration of any suitable form of delivery of dextrorphan, such as in a nasal spray comprising dextrorphan dissolved in a saline solution. 108. The method of any one of Embodiments 1-9, further comprising administration of an additional therapeutic agent before, after, or during administration of dextrorphan.

109. The method of any one of Embodiments 1-9, further comprising administration of a non drug therapy before, after, or during administration of dextrorphan.

110. The method of any one of Embodiments 11-19, further comprising administration of an additional therapeutic agent before, after, or during administration of dextrorphan.

111. The method of any one of Embodiments 11-19, further comprising administration of a non drug therapy before, after, or during administration of dextrorphan. 112. The method of any one of the preceding Embodiments, wherein the dextrorphan is administered in the form of a composition comprising dextrorphan.

113. The method of any one of the preceding Embodiments, wherein the composition further comprises an additional therapeutic agent. 114. The method of any one of the preceding Embodiments, wherein the dextrorphan is in the form of a pharmaceutically acceptable salt.

115. The method of any one of the preceding Embodiments, wherein the pharmaceutically acceptable salt is a tartrate.

EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described in the present application. Such equivalents are intended to be encompassed by the following claims.

All references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may encompass the entirety of the document.

The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

The terms “about” and “substantially” preceding a numerical value mean ±10% of the recited numerical value. Where a range of values is provided, each value between and including the upper and lower ends of the range are specifically contemplated and described herein.

Claims

1. A method of inducing a dissociative experience in an individual, comprising orally administering to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration.

2. The method of claim 1, wherein the amount is from about 150 mg to about 600 mg.

3. The method of claim 1, wherein the amount is from about 200 mg to about 500 mg.

4. The method of claim 1, wherein the amount is from about 250 mg to about 300 mg.

5. The method of claim 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 4 hours after oral administration of dextrorphan.

6. The method of claim 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

7. The method of claim 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between

0.5 hours and 1.5 hours after oral administration of dextrorphan.

8. The method of claim 1, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan.

9. The method of claim 1, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

10. The method of any one of claims 1-9, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

11. A method of inducing a dissociative experience in an individual, comprising intranasal administration to the individual an amount of dextrorphan sufficient to induce a dissociative experience within 4 hours after administration.

12. The method of claim 11, wherein the amount is from about 50 mg to about 350 mg.

13. The method of claim 11, wherein the amount is from about 100 mg to about 300 mg.

14. The method of claim 11, wherein the amount is from about 150 mg to about 250 mg.

15. The method of claim 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 4 hours after oral administration of dextrorphan.

16. The method of claim 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

17. The method of claim 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

18. The method of claim 11, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan.

19. The method of claim 11, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative

States Scale (CADSS).

20. The method of any one of claims 11-19, wherein the intranasal administration of dextrorphan is carried out by intranasal administration of any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension.

21. The method of claim 20, wherein the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea and histaminergic-release symptoms.

23. The method of claim 22, wherein the amount is from about 150 mg to about 600 mg.

24. The method of claim 22, wherein the amount is from about 200 mg to about 500 mg.

25. The method of claim 22, wherein the amount is from about 250 mg to about 300 mg.

26. The method of claim 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual between 0.5 hours and 4 hours after oral administration of dextrorphan.

27. The method of claim 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 2 hours after oral administration of dextrorphan.

28. The method of claim 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

29. The method of claim 22, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after oral administration of dextrorphan.

30. The method of any one of claims 22-29, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

31. The method of any one of claims 22-29, wherein the individual is experiencing an episode of acute suicidal ideation.

32. The method of any one of claims 22-29, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

33. The method of any one of claims 22-29, wherein the amount is sufficient to induce in the individual a dissociative experience.

34. The method of claim 33, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

35. The method of claim 22, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

36. The method of any one of claims 22-29, wherein the amount of dextrorphan from about 150 mg to about 600 mg is administered daily until the individual’s rating on a depression scale is reduced by at least 50%.

37. The method of claim 36, wherein the depression scale is selected from a group consisting of: Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Beck

Depression Inventory, empirical observation by a clinician, or self-reported scale.

38. The method of claim 37, wherein the individual has previously experienced the dissociative experience induced by dextrorphan and is subsequently administered orally a subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different drug(s) to reduce depression in the individual.

39. The method of claim 38, wherein the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg.

40. The method of claim 38, wherein the subsequent dose of dextrorphan is about 40 mg.

41. The method of any one of claims 38-40, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

42. The method of any one of claims 38-40, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

43. The method of any one of claims 38-40, wherein the individual has been previously treated for a depressive disorder by oral administration of an amount of dextrorphan from about 150 mg to about 600 mg.

44. The method of any one of claims 38-40, wherein the subsequent dose of dextrorphan does not induce in the individual a dissociative experience.

45. The method of claim 44, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS).

46. The method of any one of claims 38-40, wherein the subsequent dose of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

48. The method of claim 47, wherein the amount is from about 50 mg to about 350 mg.

49. The method of claim 47, wherein the amount is from about 100 mg to about 300 mg.

50. The method of claim 47, wherein the amount is from about 150 mg to about 250 mg.

51. The method of claim 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual between 0.5 hours and 4 hours after intranasal administration of dextrorphan.

52. The method of claim 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 2 hours after intranasal administration of dextrorphan.

53. The method of claim 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.5 hours and 1.5 hours after intranasal administration of dextrorphan.

54. The method of claim 47, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual is sufficient to induce the dissociative experience between 0.75 hours and 1.5 hours after intranasal administration of dextrorphan.

55. The method of any one of claims 47-54, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

56. The method of any one of claims 47-54, wherein the individual is experiencing an episode of acute suicidal ideation.

57. The method of any one of claims 47-54, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

58. The method of any one of claims 47-54, wherein the amount is sufficient to induce in the individual a dissociative experience.

59. The method of claim 58, wherein the dissociative experience is determined to have occurred by assessment that relies on an individual’s score on the Clinician- Administered Dissociative States Scale (CADSS).

60. The method of claim 47, wherein the intranasal administration of dextrorphan is carried out by intranasal administration of any vehicle suitable for intranasal administration, such as in an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension.

61. The method of claim 60, wherein the intranasal administration of dextrorphan is preceded, accompanied, or followed by the administration of another drug to prevent or treat side effects, such as nausea and histaminergic-release symptoms.

62. The method of any one of claims 47-54, wherein the amount of dextrorphan from about 50mg to about 350mg is administered daily until the individual’s rating on a depression scale is reduced by at least 50%.

63. The method of claim 62, wherein the depression scale is selected from a group consisting of: Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Beck

64. The method of claim 63, wherein the individual has previously experienced the dissociative experience induced by dextrorphan and is subsequently administered orally a subsequent dose of dextrorphan in an amount from about 15 mg to about 100 mg; a dose of another, different drug or drugs; or a combination of the subsequent dose of dextrorphan and the dose of one or more additional, different drug(s) to reduce depression in the individual.

65. The method of claim 64, wherein the subsequent dose of dextrorphan is an amount from about 30 mg to about 85 mg.

66. The method of claim 64, wherein the subsequent dose of dextrorphan is about 40 mg.

67. The method of any one of claims 64-66, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

68. The method of any one of claims 64-66, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

69. The method of any one of claims 64-66, wherein the individual has been previously treated for a depressive disorder by intranasal administration of an amount of dextrorphan from about 50 mg to about 350 mg.

70. The method of any one of claims 64-66, wherein the subsequent dose of dextrorphan does not induce in the individual a dissociative experience.

71. The method of claim 70, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS).

72. The method of any one of claims 64-66, wherein the subsequent dose of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

74. The method of claim 73, wherein the amount is from about 30 mg to about 85 mg.

75. The method of claim 73, wherein the amount is about 40 mg.

76. The method of any one of claims 73-75, wherein the individual has been diagnosed with major depressive disorder, treatment-resistant depression, cyclothymic disorder, bipolar spectrum disorder, premenstrual dysphoric disorder, suicidal ideation, depressed mood, or passive death wish.

77. The method of any one of claims 73-75, wherein the individual might have depressive symptoms, but the individual has not been diagnosed as having a depressive disorder.

78. The method of any one of claims 73-75, wherein the individual has been previously treated for a depressive disorder by oral administration of an amount of dextrorphan from about 150 mg to about 600 mg.

79. The method of any one of claims 73-75, wherein the individual has been previously treated for a depressive disorder by intranasal administration of an amount of dextrorphan from about 50 mg to about 350 mg.

80. The method of any one of claims 73-75, wherein the amount does not induce in the individual a dissociative experience.

81. The method of claim 80, wherein the dissociative experience is determined not to have occurred by assessment that relies on an individual’s score on the Clinician-Administered Dissociative States Scale (CADSS).

82. The method of any one of claims 73-75, wherein the oral administration of dextrorphan is administered by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

84. The pharmaceutical composition of claim 83, wherein the single oral dose of dextrorphan is a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

86. The pharmaceutical composition of claim 85, wherein the single intranasal dose of dextrorphan is an aerosol, an aqueous solution, a non-aqueous solution, a dry powder, a gel, a liposome, a nanoparticle, a droplet, a liquid jet, or a liquid solution or suspension.

87. A pharmaceutical kit for treating depression in an individual, comprising a package containing single oral dosage forms of an amount of dextrorphan from about 15 mg to about 600 mg in each single dosage form, wherein each dosage form is separately contained in a different compartment in the package and instructions for oral administration indicate not more than one dose daily.

88. The pharmaceutical kit of claim 87, wherein each oral dosage form of dextrorphan is a single dosage suitable for oral administration, such as a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

89. The pharmaceutical kit of claim 87, wherein single oral dosage forms of an amount of dextrorphan are labeled initial dose or subsequent dose.

90. The pharmaceutical kit of claim 89, wherein the initial dose is an amount of dextrorphan from about 150 mg to about 600 mg.

91. The pharmaceutical kit of claim 90, wherein the amount of dextrorphan in the initial dose is sufficient to induce a dissociative experience in an individual within 4 hours of administration.

92. The pharmaceutical kit of any one of claims 87-91, wherein the instructions state that the initial dose should be administered intermittently until an individual’s score on a depression rating scale is reduced by at least 50%.

93. The pharmaceutical kit of claim 89, wherein the subsequent dose is an amount of dextrorphan from about 15 mg to about 100 mg.

94. The pharmaceutical kit of claim 93, wherein the amount of dextrorphan in the subsequent dose is not sufficient to induce a dissociative experience in an individual.

95. The pharmaceutical kit of claim 94, wherein the instructions state that the subsequent dose should be administered daily until an individual does not experience depressive symptoms in the absence of the dose.

97. The method of claim 96, wherein the amount is from about 150 mg to about 600 mg.

98. The method of claim 96, wherein the amount is from about 200 mg to about 500 mg.

99. The method of claim 96, wherein the amount is from about 250 mg to about 300 mg.

100. The method of claim 96, wherein the individual reports a CADSS score of 1 within 1.5 hours after administration.

101. The method of claim 96, wherein the individual reports a CADSS score of 2 within 1.5 hours after administration.

102. The method of claim 96, wherein the individual reports a CADSS score of 3 within 1.5 hours after administration.

103. The method of claim 96, wherein the individual reports a CADSS score of 4 within 1.5 hours after administration.

104. The method of claim 96, wherein the individual reports a CADSS score of 5 within 1.5 hours after administration.

105. The method of claim 96, wherein the amount produces a concentration of dextrorphan in blood or cerebrospinal fluid of the individual sufficient to induce the dissociative experience as measured by a CADSS score between 0.5 hours and 1.5 hours after oral administration of dextrorphan.

106. The method of any one of claims 96-105, wherein the oral administration of dextrorphan is carried out by oral administration of any suitable form of delivery of dextrorphan, such as in a solid tablet, a powder, a dissolvable capsule, a soft gel, or a liquid solution or suspension.

107. The method of any one of claims 96-105, wherein the nasal administration of dextrorphan is carried out by intranasal administration of any suitable form of delivery of dextrorphan, such as in a nasal spray comprising dextrorphan dissolved in a saline solution.

108. The method of any one of claims 1-9, further comprising administration of an additional therapeutic agent before, after, or during administration of dextrorphan.

109. The method of any one of claims 1-9, further comprising administration of a non-drug therapy before, after, or during administration of dextrorphan.

110. The method of any one of claims 11-19, further comprising administration of an additional therapeutic agent before, after, or during administration of dextrorphan.

111. The method of any one of claims 11-19, further comprising administration of a non-drug therapy before, after, or during administration of dextrorphan.