Oral transmucosal esketamine therapy for alcohol use disorder and substance use disorders

Abstract

Provided herein are methods of treating alcohol use disorder (AUD), opioid use disorder (OUD), and other substance use disorders (SUDs) in a subject, for example by administering an oral transmucosal dosage form of esketamine, such as an oral thin film (OTF) form of esketamine, sublingually or buccally. Disclosed methods may combine one or more therapy modalities provided before, during, and / or after drug administration. In some aspects, the methods comprise administering a dose of esketamine that is sufficient to produce dissociative effects in a subject. In some further aspects, the methods comprise the use of specific therapy modalities or ketamine-assisted psychotherapy (KAP) protocols, including manualized relapse prevention cognitive behavioral therapy (CBT). In yet further aspects, the methods comprise ongoing support, including additional psychotherapy and / or adjunct medication, such as naltrexone, buprenorphine, buprenorphine-naloxone, disulfiram, naloxone, and others.

Description

CROSS-REFERENCE

[01] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Appl. No. 63 / 624,785, filed January 24, 2024, and hereby incorporated by reference for all purposes as if fully set forth herein. FIELD OF THE INVENTION

[02] This disclosure relates to methods of treating alcohol use disorder (AUD) and other substance use disorders (SUDs) in a subject, such as by administering oral transmucosal esketamine together with therapy. BACKGROUND OF THE INVENTION

[03] Substance use disorders (SUDs) are mental health disorders that affect an individual’s brain and behavior, resulting in an inability to control the use of substances such as alcohol or legal and illegal drugs. SUDs, particularly in their more severe forms, also can be referred to as addictions. SUDs can lead to serious personal health issues as well as public health and social problems. Prolonged use of addictive substances can cause changes in the central nervous system, resulting in intense drug cravings and a heightened risk of relapse (Compton et al. J Clin Psych. 2005;66(6):677-85). In general, the symptoms of SUDs can be severe, adherence to treatment can be challenging, and the risk of relapse can persist throughout one’s lifetime.

[04] Alcohol use disorder (AUD) is one of the most prevalent mental health disorders and SUDs globally. Individuals with AUD generally have impaired control over alcohol consumption and exhibit a chronic and often escalating pattern of alcohol use, despite consequences to their health, their relationships, and society.

[05] AUD is a significant public health burden, exerting substantial societal and economic costs.

[06] Opioid use disorder (OUD), involving the chronic use of opioids, such as heroin, morphine, codeine, fentanyl, and oxycodone, causes clinically significant distress or impairment, with symptoms that can include an overpowering desire to use opioids, increased tolerance, and withdrawal when opioids are discontinued.

[07] OUD affects 16 million people worldwide and causes more than 120,000 deaths every year.

[08] Like AUD and other SUDs, OUD can range from dependence to what is often termed “addiction.”

[09] Existing treatments for SUDs, such as behavioral therapies and pharmacological interventions, are limited in their effectiveness, with the majority of those entering treatment relapsing within 1 year. High relapse rates have been attributed to an interplay of different factors, such as poor self-efficacy, inadequate support for underlying psychological issues such as depression, behavioral rigidity, and a poor sense of self.

[10] Individuals struggling with SUDs notably include armed forces veterans and first responders. For example, despite attempts by the Veterans Association and other agencies, the rates of SUDs in veterans continues to rise. One study of military personnel found that about 30% of suicides were preceded by alcohol or drug use (Teeters et al. Subst Abuse Rehabil. 2017;8:69-77). A 2019 survey found that 4 in 5 U.S. veterans struggle with alcohol use, 1 in 4 struggle with drug use, and 1 in 13 struggle with both drug and alcohol use. WO 2025 / 160483                                   PCT / US2025 / 013057 Approximately 600,000 veterans (2.9% of the total veteran population) struggle with opioid use (Substance Abuse & Mental Health Services Admin., 2019 Nat’l Survey on Drug Use & Health: Veteran Adults (2020)).

[11] Ketamine is an A / -methyl-D-aspartate (NMDA) receptor antagonist with well-established safety and efficacy as an analgesic and anesthetic. Recent ketamine research includes studies involving participants with a range of psychiatric disorders, including SUDs. Studies relating to SUDs however have investigated ketamine that is typically administered intravenously or intramuscularly, and which still demonstrate identifiable shortcomings, as many or most subjects still relapse or suffer from continued substance craving.

[12] Consequently, there is a continued need for additional and alternative approaches to treat SUDs.

[13] Provided herein are methods to meet this need and others. For example, the disclosed methods of administering oral thin film (OTF) esketamine sublingually or buccally, and at specific dosages, together with specific therapy modalities and protocols, such as in combination with the disclosed manualized relapse prevention cognitive behavioral therapy (CBT), show advantages in clinical use, patient compliance, and efficacy in the treatment of SUDs such as AUD and OUD, and represent a way to dramatically widen access to ketamine treatment, and to reach more patients who desperately need a life-saving SUD or addiction treatment. Other advantages and improvements will become readily apparent through the disclosure below. INCORPORATION BY REFERENCE

[14] Each cited patent, publication, and non-patent literature is hereby incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. No such citation however should be construed as an admission that a cited reference is from an area that is analogous or directly applicable to the disclosure, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art. Nor should any citation be construed as the sole source of information for any point; consequently, it will be understood as being preceded by the implied signal “see, e.g.,” unless the context clearly indicates otherwise. BRIEF SUMMARY OF THE INVENTION

[15] The following presents a simplified summary of some embodiments of the invention in order to provide a basic understanding of the invention. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or delineate the scope thereof. Its purpose is to present some embodiments of the invention in a simplified form as a prelude to the detailed description.

[16] In some aspects are disclosed methods of treating a substance use disorder (SUD) in a subject in need thereof, comprising: (a) administering, during a drug-administration session, one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof; (b) wherein the one or more pharmaceutical compositions are formulated as an oral transmucosal dosage form, suitable for buccal or sublingual administration; (c) wherein the oral bioavailability of the esketamine is at least 25%; and (d) wherein the one or more compositions provide a dose of esketamine sufficient to produce dissociative effects or a mystical experience in the subject. In embodiments, the oral transmucosal dosage form is any of a tablet, a film, WO 2025 / 160483                                   PCT / US2025 / 013057 a lozenge, a gum, a spray, a gel, a cream, an ointment, a powder, a granule, a patch, a strip, a sachet, a pouch, an oral solution, and a suspension. In embodiments, the film is an esketamine oral thin film (OTF).

[17] In embodiments, the SUD is any of alcohol use disorder (AUD); opioid use disorder (OUD); nicotine dependence or tobacco use disorder; sedative, hypnotic, and anxiolytic use disorder; stimulant use disorder; cannabis use disorder; hallucinogen use disorder; inhalant use disorder; and other substance use disorder. In embodiments, the SUD is alcohol use disorder (AUD). In embodiments, the AUD is harmful use or dependent use AUD, alcohol abuse, alcohol dependence, or alcoholism. In embodiments, the AUD is classified as mild, moderate, or severe according to DSM-5. In embodiments, the SUD is opioid use disorder (OUD).

[18] In some embodiments, the esketamine is administered in a dose of between about 100 mg and about 200 mg, between about 100 mg and about 125 mg, between about 125 mg and about 150 mg, between about 150 mg and about 175 mg, or between about 175 mg and about 200 mg. In some embodiments, the dose of esketamine is between about 110 mg and about 120 mg, or between about 170 mg and about 180 mg. In some embodiments, the dose of esketamine is about 115.3 mg. In some embodiments, the dose of esketamine is about 172.95 mg. In some embodiments, the one or more pharmaceutical compositions are two esketamine OTFs each comprising 57.65 mg of esketamine, for a total dose of esketamine of 115.3 mg. In some embodiments, the one or more pharmaceutical compositions are three esketamine OTFs each comprising 57.65 mg of esketamine, for a total dose of esketamine of 172.95 mg.

[19] In some embodiments, producing dissociative effects or a mystical experience in the subject is determined using a psychometric rating scale. In some embodiments, the psychometric rating scale is any one or more of the Hallucinogen Rating Scale (HRS), the Mystical Experience Questionnaire (MEQ), and the Addiction Research Center Inventory (ARCI).

[20] In some embodiments, the method is effective to: (a) reduce use of a substance, (b) reduce cravings for a substance, (c) promote abstinence from a substance, (d) prevent relapse into use of a substance, (e) improve a symptom of the SUD, (f) reduce the severity of a diagnostic criterion of the SUD, (g) improve a score on an assessment, or (h) improve a score or result on an outcome measure. In some embodiments, the assessment is any of the Severity of Alcohol Dependence Questionnaire (SADQ), the Mini International Neuropsychiatric Interview 5 (MINI 5), the Columbia Suicide Severity Rating Scale (C-SSRS), the Alcohol Dependence Syndrome section of the SCID-5-CT (Clinical Trials Version), the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7 (GAD-7), the Short Inventory of Problems for Alcohol (SIP), the Alcohol Timeline Follow Back (TLFB), the Clinical Institute Withdrawal Assessment for Alcohol—Revised Version (CIWA-Ar), the Penn Alcohol Craving Scale (PACS), the Obsessive Compulsive Drinking Scale (OCDS), the Pittsburgh Sleep Quality Index (PSQI), the Interpersonal reactivity Index (IRI), the Short Form (36) Health Survey (SF-36), the Self-Compassion Scale (SCS), and the Trauma History Questionnaire (THQ).

[21] In some embodiments, the outcome measure is any of increased decentering, increased awe, increased positive affect, decreased negative affect, decreased experiential avoidance, increased frequency of mystical-type experiences, reduction of substance use, reduction of substance cravings, a promotion of substance use abstinence, a prevention of relapse into substance use, an improvement of at least one symptom of substance use disorder, an increase in quality of life, an increase in psychosocial functioning, a decrease in use or frequency of a prescription medication, a decrease in use or frequency of a recreational drug, a decrease in obsessive compulsive thoughts, a decrease in suicidality, an increase in feelings of empathy, an increase in self-compassion, a reduction in the frequency of substance use, a reduction in drive or urge to engage in substance use, prolonged abstinence from substance use, reduction in severity of symptoms of substance use, and reduction in the time spent on substance use.

[22] In some embodiments, the disclosed methods further include adjunctive psychotherapy. In some embodiments, the adjunctive psychotherapy is a psychosocial or behavioral therapy. In some embodiments, the psychosocial or behavioral therapy is a ketamine-assisted psychotherapy (KAP), a mindfulness-based intervention, a standardized psychological treatment, motivational interviewing, Internal Family Systems (IFS) therapy, or any combination thereof. In some embodiments, the mindfulness-based intervention is MindfulnessBased Relapse Prevention (MBRP), Mindfulness-Based Stress Reduction (MBSR), Mindfulness-Based Cognitive Therapy (MBCT), Dialectical Behavior Therapy (DBT), Acceptance and Commitment Therapy (ACT), Mindfulness Interviewing, and Cognitive Behavioral Therapy (CBT), or any combination thereof. In some embodiments, the KAP is KAP based on the protocols of Ketamine for reduction of Alcohol Relapse (KARE) or KAP based on the KARE Therapy Programme Guidebook.

[23] In some embodiments, the subject has a comorbid mental health disorder, a comorbid behavioral addiction, or a comorbid neurodegenerative disorder. In some embodiments, the comorbid mental health disorder is any of post-traumatic stress disorder (PTSD), an adjustment disorder, an affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, a phobia disorder, a binge disorder, body dysmorphic disorder, a mood disorder related to another health condition, a disruptive behavior disorder, an eating disorder, an impulse control disorder, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), a personality disorder, an attachment disorder, or a dissociative disorder. In some embodiments, the comorbid behavioral addiction is any of gambling disorder, compulsive sexual behavior disorder, compulsive buying-shopping disorder, internet addiction, gaming disorder and internet gaming disorder, risk-taking addictions, kleptomania, pyromania, pornography addiction, technology addiction, binge eating disorder, “workaholism,” perfectionism, pathological skin picking, exercise addiction, tanning addiction, tattoo addiction, masturbation addiction, sex addiction, and love addiction.

[24] In some embodiments, the comorbid neurodegenerative disorder is any of Alzheimer’s disease, amyotrophic lateral sclerosis, Charcot’s disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, WO 2025 / 160483                                   PCT / US2025 / 013057 Parkinson’s disease, Parkinsonisms, prion disease, progressive supranuclear palsy, and traumatic brain injury (TBI), including mild traumatic brain injury (mTBI). In embodiments, administering one or more pharmaceutical compositions comprising esketamine according to the disclosed methods also treat the comorbid mental health disorder, the comorbid behavioral addiction, or the comorbid neurodegenerative disorder.

[25] In embodiments, the methods further comprise a second drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject. In embodiments, the methods further comprise a third drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject. In embodiments, the methods further comprise a fourth drugadministration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject. In embodiments, the methods further comprise a fifth drug-administration session, wherein one or more compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[26] In some embodiments, the methods further comprise providing the subject with one or more sessions of adjunctive psychotherapy separate from the drug-administration session.

[27] In some embodiments, the methods further comprise administering to the subject an additional active agent. In some embodiments, the additional active agent is any of an amino acid, an antioxidant, an antiinflammatory agent, an analgesic, an antineuropathic or antinociceptive agent, an antimigraine agent, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, a cannabinoid, a dissociative, an immunostimulant, an anti-cancer agent, an antiemetic, a hormone, an orexigenic, an antiulcer agent, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotectant, an entactogen or empathogen, an entheogen, a psychedelic, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenethylamine, a sedative, a serotonergic agent, a hypnotic, an analeptic, a psychoneurotropic, a neuro-muscle blocker, an antispasmodic, an antiallergic, a cardiotonic, an antiarrhythmic, a diuretic, a hypotensive, a vasopressor, an antitussive, an antidiabetic, an antitumor agent, a chemotherapeutic, a narcotic, a stimulant, a vitamin, a SSRI, a SNRI, a NRI, a NDRI, a TCA, a benzodiazepine, an opioid antagonist, a CB1 antagonist, a CRH1 receptor antagonist, a NK1R antagonist, an OTR agonist, a GABA agent, a voltage-gated sodium channel inhibitor, a voltage-dependent calcium channel agonist, an a7 nicotinic acetylcholine receptor agonist, a 5-HT3 antagonist, a 5-HT1A receptor partial agonist, a 5-HT2A receptor antagonist, a 5-HT reuptake inhibitor, a SERT inhibitor, an a1 adrenoreceptor antagonist, a glucocorticoid receptor antagonist, an a1 adrenoreceptor agonist, an AChE inhibitor, a dopamine D2 receptor antagonist, an a2 adrenoreceptor agonist, a NMDA modulator, an aldehyde dehydrogenase inhibitor (e.g., disulfiram), a phenylethylamine, and a serotonergic agent, or a pharmaceutically acceptable salt thereof.

[28] In further aspects are disclosed pharmaceutical compositions comprising esketamine formulated as an oral transmucosal dosage form, for use in any of the disclosed methods. In some further aspects are disclosed WO 2025 / 160483                                   PCT / US2025 / 013057 pharmaceutical compositions, wherein the oral transmucosal dosage form is an oral thin film (OTF). In yet further aspects are disclosed the use of a pharmaceutical composition comprising esketamine, formulated as an oral transmucosal dosage form, in the treatment of an SUD according to the disclosed methods. In some embodiments, the SUD is AUD or OUD.

[29] The foregoing has outlined broadly and in summary certain pertinent features of the invention so that the detailed description that follows may be better understood, and the contribution to the art more fully appreciated. This summary is a brief and general synopsis of only some of the aspects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are entitled. Additional features of the invention are described hereinafter. It should be appreciated that all disclosed aspects and embodiments are only exemplary, and may be readily utilized as a basis for modifying or designing other aspects and embodiments for carrying out the same purposes. Such equivalent aspects and embodiments will be appreciated to be also within the scope and spirit of the invention, which will be known by the claims.

[30] The headings are only used to expedite review by a reader, and not to limit the invention in any way. BRIEF DESCRIPTION OF THE FIGURES [31 ] To further clarify various aspects of the invention, a more particular description is rendered by reference to certain exemplary embodiments illustrated in the figures. It will be appreciated that these figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. They are merely provided as exemplary illustrations of certain concepts of some embodiments of the invention. These figures, and the elements depicted therein, are not necessarily drawn to consistent scale or to any scale. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[32] FIG. 1 depicts a flow diagram of the protocol design of the study described in Example 1.

[33] FIG. 2 depicts the alcohol intake over time for Participant 1 as described in Example 1.

[34] FIG. 3 depicts the alcohol intake over time for Participant 2 as described in Example 1.

[35] FIG. 4 depicts the alcohol intake over time for Participant 3 as described in Example 1.

[36] FIG. 5 depicts the alcohol intake over time for Participant 4 as described in Example 1.

[37] FIG. 6 depicts an experiential avoidance plot for Participant 1 as described in Example 1.

[38] FIG. 7 depicts an experiential avoidance plot for Participant 2 as described in Example 1.

[39] FIG. 8 depicts an experiential avoidance plot for Participant 3 as described in Example 1.

[40] FIG. 9 depicts an experiential avoidance plot for Participant 4 as described in Example 1.

[41] FIG. 10 depicts a decentering plot for Participant 1 as described in Example 1.

[42] FIG. 11 depicts a decentering plot for Participant 2 as described in Example 1.

[43] FIG. 12 depicts a decentering plot for Participant 3 as described in Example 1.

[44] FIG. 13 depicts a decentering plot for Participant 4 as described in Example 1. WO 2025 / 160483                                   PCT / US2025 / 013057

[45] FIG. 14 depicts alcohol craving plots for participants 1-4 (A-D, respectively) as described in Example 1.

[46] FIG. 15 depicts positive affect plots for participants 1-4 (A-D, respectively) as described in Example 1.

[47] FIG. 16 depicts negative affect plots for participants 1-4 (A-D, respectively) as described in Example 1.

[48] FIG. 17 depicts awe plots for participants 1-4 (A-D, respectively) as described in Example 1.

[49] FIG. 18 depicts the changes in plasma concentrations of esketamine and its metabolites over time after administration of 50 mg oral thin film (OTF) esketamine as individual values, described in Example 3. Figures depict all OTF combined (A; n = 19), OTF sublingual (B; n = 14), and OTF buccal (C; n = 5).

[50] FIG. 19 depicts the changes in plasma concentrations of esketamine and its metabolites over time after administration of 50 mg oral thin film (OTF) esketamine as average values ± 95% confidence interval (c.i.), described in Example 3. Figures depict all OTF combined (D; n = 19), OTF sublingual and buccal (B; n = 14 and 5, respectively), and OTF buccal (0; n = 5). [51 ] FIG. 20 depicts the changes in plasma concentrations of esketamine and its metabolites over time after administration of 100 mg OTF esketamine as individual values, described in Example 3. Figures depict all OTF combined (A; n = 20), OTF sublingual (B; n = 15), and OTF buccal (C; n = 5).

[52] FIG. 21 depicts the changes in plasma concentrations of esketamine and its metabolites over time after administration of 100 mg OTF esketamine as average values ± 95% confidence interval (c.i.), described in Example 3. In panel E, OTF and buccal forms are shown. Figures depict all OTF combined (D; n = 20), OTF sublingual and buccal (E; n = 15 and 5, respectively), and OTF buccal (F; n = 5).

[53] FIG. 22 depicts a comparison of the 50 and 100 mg esketamine OTF pharmacokinetic data in the complete data set. Data are mean ± 95% confidence interval. DETAILED DESCRIPTION OF THE INVENTION

[54] While various embodiments and features of certain aspects are summarized above, this description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. The scope of the invention includes all aspects and embodiments thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as recited in the below or other claims. A. General Definitions and Terms

[55] The singular forms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Thus, “a compound” includes reference to not only one but also to two or more compounds, and “an excipient” includes reference to not only one but also to two or more excipients. While the term “one or more” also may be used, its absence (or its replacement by the singular “a” or “an”) does not signify the singular only, but simply provides emphasis to the possibility of multiples in some particular embodiments. WO 2025 / 160483                                   PCT / US2025 / 013057

[56] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise.

[57] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[58] A shorthand may be used for some terms and, unless context clearly indicates otherwise, will have the same meaning as the full term. For example, a “pharmaceutical composition” may be referred to simply as a “composition,” and other such shorthand terms will be readily appreciated in view of the disclosure.

[59] Unless context indicates a distinction relevant to a described or claimed embodiment, a “composition” and a “formulation,” when used as nouns, are used interchangeably and equivalently herein.

[60] “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.” [61 ] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[62] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, should be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers should be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, the term “about 1, 2, or 3” is understood to mean “about 1, about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.” The term “substantially,” where it is used to modify a feature or limitation, must be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the relevant art.

[63] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the disclosure, e.g., medicine, biology, pharmacology, chemistry, statistics, and the like, and that will be well known and commonly employed in such fields. Standard techniques and procedures are those generally performed according to conventional methods in the art.

[64] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs (as shorthand, “one of skill”).

[65] Further definitions to assist a reader in understanding the embodiments are below and throughout; WO 2025 / 160483                                   PCT / US2025 / 013057 however, it will be appreciated that such definitions are not intended to limit the scope of the disclosure, which is properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[66] Additional definitions and abbreviations are provided elsewhere herein. B. Ketamine, Esketamine, and Other Compounds

[67] In some aspects are provided methods comprising administration of one or more compounds.

[68] In embodiments, the compound is a NMDA antagonist. A “W-methyl-D-aspartate” (or “NMDA”) “receptor antagonist” (equivalently, an “NMDA antagonist” or “NMDAR antagonist”) is a drug that antagonizes the N-methyl-D-aspartate receptor (NMDAR). Certain NMDA antagonists, at sufficiently high doses, can induce dissociative anesthesia, while providing mildly stimulating effects at lower (subanesthetic) doses. In embodiments, the NMDA antagonist is ketamine. In embodiments, the NMDA antagonist is esketamine.

[69] “Ketamine” refers to the compound 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone.

[70] Ketamine, a chiral compound, exists as two stereoisomers: S(+)-ketamine and R(-)-ketamine. [71 ] Herein, reference to the S(+) stereoisomer of ketamine (equivalently, “(S)-ketamine,” “S-ketamine,” or “esketamine”), refers to the compound (2S)-2-(2-chlorophenyl)-2-(methylamino)-cyclo-hexanone.

[72] Herein, reference to the R(-) stereoisomer of ketamine (equivalently, “(R)-ketamine,” “R-ketamine,” or “arketamine”), refers to the compound (2R)-2-(2-chlorophenyl)-2-(methylamino)-cyclo-hexanone.

[73] In some alternative embodiments, where a disclosed composition comprises ketamine or esketamine, another NMDA antagonist, or another NMDA modulator, is used in place of ketamine or esketamine.

[74] An “NMDA modulator” includes compounds that bind to, block, or otherwise influence (e.g., via an allosteric reaction) activity at the NMDA receptor. In embodiments, the NMDA modulator is a partial NMDA receptor agonist, such as D-cycloserine (DCS). In embodiments, the NMDA modulator is a partial agonist and is NRX-1074 or rapastinel (GLYX-13). In embodiments, the NMDA modulator is any of plazinemdor, rapastinel, LY-2140023, NYX-458, NYX-783, NYX-2925, NRX-1074, SAGE-718, a substituted 1,2,3-triazole NMDA modulator such as disclosed in WO2017 / 139428, a spiro-lactam NMDA modulator such as disclosed in WO2018 / 026798, and an NMDA modulator disclosed in WO2017 / 066590 (e.g., at

[0006] ).

[75] An “NMDA antagonist” is a compound that antagonizes, or inhibits the action of, the NMDA receptor. NMDA antagonists will be known to one of skill, and can be found, for example, on DrugBank (see, e.g., Accession Number DBCAT002723, https: / / go.drugbank.com / categories / DBCAT002723). Examples are also provided herein. In embodiments, the NMDA antagonist is a ketamine metabolite. The ketamine metabolite may be norketamine, a dehydronorketamine, a hydroxyketamine, or a hydroxynorketamine, including isomers thereof. The ketamine metabolite may be any of the 12 HNK metabolites formed from the metabolism of ketamine in vivo, including any of the stereoselective metabolites of esketamine or arketamine, such as (R,S)-norketamine (NK), (R,S)-dehydronorketamine, hydroxyketamines, and hydroxynorketamines (HNKs), including (2S,6S;2R,6R)-HNK, (2R,4R;2S,4S-2S,6R;2R,6S)-HNK, and (2R,4S;2S,4R-2S,5S;2R,5R)-HNK (see Farmer 2020), and 2R,6R-hydroxynorketamine, as well as its prodrugs (see US2019 / 0380978), 2S,6S-hydroxynorketamine (see US2020 / 0157040), as well as conformationally stabilized analogs of ketamine metabolites, such as 6-hydroxyketamine and 6-hydroxynorketamine (see WO2018 / 104729), and dehydronorketamines (DHNKs), such as R-5,6-DHNK and S-5,6-DHNK (see WO2019 / 058145).

[76] In embodiments, the NMDA antagonist is memantine, amantadine, rimantadine, nitromemantine (YQW-36), or acamprosate. In embodiments, the NMDA antagonist is dextromethorphan (DXM), dextrorphan, or dextrallorphan (DXA). In embodiments, the NMDA antagonist is pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, or ketobemidone. In embodiments, the NMDA antagonist is ephenidine (NEDPA, EPE), p-keto-ephenidine, diphenidine (1,2-DEP, DPD, DND), isopropylphenidine (NPDPA), methoxphenidine (MXP), fluorolintane (2-FPPP, 2-F-DPPy), remacemide, or another diarylethylamine. In embodiments, the NMDA antagonist is gacyclidine (GK-11), neramexane, lanicemine (AZD6765), dizocilpine (MK-801), 8a-phenyl-decahydroquinoline (8A-PDHQ), remacemide, ifenprodil, traxoprodil (CP-101,606), eliprodil (SL-82.0715), etoxadrol (CL-1848C), dexoxadrol, WMS-2539, NEFA, delucemine (NPS-1506), aptiganel (Cerestat; CNS-1102), midafotel (CPPene; SDZ EAA 494), dexanabinol (HU-211 or ETS2101), selfotel (CGS-19755), 7-chlorokynurenic acid (7-CKA), 5,7-dichlorokynurenic acid (5,7-DCKA), L-683344, L-689560, L-701324, GV150526A, GV196771A, CERC-301 (MK-0657), atomoxetine, LY-235959, CGP 61594, CGP 37849, CGP 40116 or CGP 37849, LY-233536, PEAQX (NVP-AAM077), Ro 25-6981, GW468816, EVT-101, indantadol, perzinfotel (EAA-090), SSR240600, 2-MDP (U-23807A) or AP-7.

[77] In embodiments, the NMDA antagonist is a ketamine analog (e.g., tiletamine), phencyclidine (PCP), a phencyclidine analog (e.g., tenocyclidine, eticyclidine, rolicyclidine), methoxetamine (2-MeO-2-deschloro-ketamine, MXE), or a methoxetamine analog. In embodiments, the ketamine analog is DXE (2'-Oxo-PCM, DCK), 3-MeO-PCE, KEA-1010, deschloroketamine (2-phenyl-2-methylamino-cyclohexanone), N-ethyl-deschloroketamine (2'-Oxo-PCE, O-PCE), 2-fluoro-deschloroketamine (2-FDCK), or alkyne-norketamine (A-NK). In embodiments, the NMDA antagonist is an arylcyclohexylamine or an arylcyclohexylamine derivative, such as disclosed in WO2022 / 047256, US2022 / 0041540, and WO2021 / 255737. In embodiments, the NMDA antagonist is ibogaine, noribogaine, an ibogaine metabolite, or an ibogaine derivative or analog.

[78] Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to a pharmaceutical composition comprising the compound, i.e., “ketamine” may mean “a pharmaceutical composition comprising ketamine.” Reference to a compound moreover also may refer to a specific pharmaceutical composition, i.e., “esketamine” may mean “an oral thin film comprising esketamine.”

[79] Unless context clearly indicates otherwise, reference to a composition “comprising” a compound should be understood as also referring to a composition “consisting essentially of” said compound. For example, “esketamine” thus may mean “a pharmaceutical composition consisting essentially of esketamine.”

[80] Unless context clearly indicates otherwise, reference to a stereoisomer of a compound should be WO 2025 / 160483                                   PCT / US2025 / 013057 understood as also referring to a composition comprising the compound in substantially pure or pure enantiomeric form. For example, reference to “esketamine” may mean a composition comprising a substantially pure or pure S(+) enantiomer of ketamine. [81 ] A “substantially pure” enantiomer, such as a S(+) enantiomer of ketamine, may refer, in embodiments, to a mixture of esketamine and arketamine in a defined ratio, such as a molar ratio or a weight ratio, and with or without any salt(s), wherein the S:R ratio is greater than 90:1, 95:1, 96:1, 97:1, 98:1, or 99:1.

[82] A “pure” enantiomer, such as a S(+) enantiomer of ketamine, may refer, in embodiments, to a sample that contains only esketamine, without any detectable amount of arketamine, within the limits of analytical detection, or in a defined ratio, such as greater than 100:1, greater than 500:1, or greater than 1000:1.

[83] In embodiments, “esketamine” thus will refer to a composition comprising no measurable arketamine.

[84] In embodiments, reference to an enantiomer will refer to a composition comprising a purity of about 100% of the enantiomer. For example, “esketamine” may refer to a composition of about 100% esketamine.

[85] “Purity” also may refer to enantiomeric purity, and for example “esketamine” may mean a composition having an enantiomeric excess (ee) of esketamine of about 100%, or of 100%. A “substantially pure” enantiomer also may refer to enantiomeric purity. For example, “esketamine” may refer, in embodiments, to a composition comprising esketamine having an enantiomeric excess (ee) of at least 90%, at least 92.5%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[86] Unless context clearly indicates otherwise, reference to a chiral compound should be understood as also referring to a racemate of the compound. Thus for example, “ketamine” may mean “racemic ketamine.”

[87] Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to its pharmaceutically acceptable salts, i.e., “ketamine” may mean “ketamine, or a pharmaceutically acceptable salt thereof’; “esketamine” may mean “esketamine, or a pharmaceutically acceptable salt thereof.” “Ketamine” and “esketamine” therefore may mean “ketamine HCI” and “esketamine HCI” respectively.

[88] Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to the compound as a hydrate, solvate, co-crystal, or crystalline polymorph, or in amorphous form.

[89] Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to a tautomer or structural isomer of the compound. Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to an isotopologue of the compound, such as the compound deuterated at one or more positions. Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to a prodrug of the compound. Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to a metabolite of the compound, such as an active metabolite of the compound. Unless context clearly indicates otherwise, reference to a compound should be understood as also referring to a derivative or analog of the compound.

[90] Any such reference as described above also refers to combinations of any of the foregoing thereof. [91 ] Where a disclosed compound includes its pharmaceutically acceptable salts, such as salts of ketamine and esketamine, the term “pharmaceutically acceptable salt” will refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Such salts may be prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; exemplary nonaqueous solvents include ether, ethyl acetate, ethanol, isopropanol, and acetonitrile. For therapeutic use, salts of a compound are those wherein the counter-ion is pharmaceutically acceptable. One of ordinary skill can select from among a wide variety of available counterions those that are pharmaceutically acceptable. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc, and the like (see generally, Berge etal. J Pharm Sci. 1977;66(1): 1-19).

[92] Disclosed compounds, such as ketamine and esketamine, may exist in a solid state in crystalline or noncrystalline form, or as a mixture thereof. Disclosed compounds may include pharmaceutically acceptable solvates, which may be formed for crystalline or non-crystalline compounds. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate. Where the solvent is water, a solvate may be referred to as a hydrate. Solvates and hydrates include those with stoichiometric ratios of the solvent, as well as compositions containing variable amounts of the solvent.

[93] Also provided are solid forms or solid compositions of compounds. For example, compounds may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms and nano- particulate forms, all of which are within the disclosure. In addition, compounds include crystalline forms, or polymorphs, having different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility, and where various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. One of skill will recognize that certain crystalline forms or other forms may provide advantages.

[94] An “isotopologue” of a compound refers to the compound with at least one isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched. By way of example, isotopes of hydrogen including deuterium (2H) and tritium (3H) may be used anywhere that achieves the desired result. Alternatively or in addition, isotopes of carbon, e.g., 13C and 14C, may be used. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is at least 60%, 70%, 80%, 90%, 95%, or 99% or more enriched in an isotope at any location of interest. In one embodiment, deuterium is 90%, 95%, or 99% enriched at a desired location. Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements and thus may be preferred in some circumstances. Isotopologs of a disclosed compound generally can be prepared by carrying out a known synthesis, but substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[95] A “prodrug” of a compound refers to a precursor of the compound which undergoes, or may undergo, a chemical or a metabolic conversion to become the compound. A prodrug can be converted ex vivo to the compound by chemical transformative processes. In vivo, a prodrug is converted to the compound by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety to form the compound. In embodiments, a prodrug of a disclosed compound comprises a biologically labile group on a functional moiety (e.g., an amine) of the compound. Included are prodrugs that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the compound. Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. Such groups can be attached to a compound via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion.

[96] For ketamine, esketamine, or any other disclosed compound, substitution of the compound by its ion, free base, salt, hydrate, solvate form, co-crystal, crystalline polymorph, amorphous form, tautomer, structural isomer, stereoisomer, enantiomerically enriched mixture, isotopologue, deuterated variant, prodrug, active metabolite, derivative, or analog, including all combinations of any of the foregoing, and in pure or substantially WO 2025 / 160483                                   PCT / US2025 / 013057 pure form, accordingly will be understood to provide alternative embodiments also within the scope of the disclosure, and with modifications, if necessary or desired, such as to the manner of formulation, route of administration, and dosage, made according to the disclosure and the general knowledge in the art.

[97] A disclosed compound, such as ketamine or esketamine, may be administered as part of a pharmaceutical composition, but may be prepared for inclusion in the composition as an isolated or purified compound. Herein, the terms “isolated,” “purified,” and “substantially pure” refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a compound may be defined as having a chromatographic purity (of the compound) of greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%, as determined by area normalization of an HPLC profile or similar method.

[98] In embodiments, compounds are produced and tested in compliance with Good Laboratory Practice (GLP) or Good Manufacturing Practice (GMP) requirements, or equivalents, including any related practices.

[99] Disclosed compounds, unless expressly provided otherwise, may be provided in compositions that are open-ended and may comprise additional compounds, active or inactive agents, and other ingredients. C. Additional Active Agents

[100] A composition comprising a disclosed compound, as described herein, may further comprise one or more additional active agents. An additional active agent may, for example, contribute to, enhance, or provide an additional therapeutic effect, or contribute to or provide a synergistic effect or additional synergistic effect.

[101] An additional active agent may decrease an unwanted effect, improve bioavailability, increase plasticity (e.g., neuroplasticity or metaplasticity), alter a property in a desirable way, such as pharmacokinetics (PK) or pharmacodynamics (PD), or modulate a desired system or pathway (e.g., a neurotransmitter system).

[102] A “therapeutic effect” generally will refer to the response(s) in a subject after treatment that are judged to be desirable and beneficial. Hence, depending on the disorder(s) to be treated, and depending on the active agent(s) administered, such responses may differ, but the responses will be readily appreciated by those of skill, and will be understood based on the teachings herein and the general knowledge in the art.

[103] Measures of therapeutic effect include outcome measures, endpoints, effect measures, and other measures of effect within clinical or medical practice or research which are used to assess an effect, both positive and negative, of an intervention or treatment, whether subject-reported, gathered through laboratory tests such as blood work, urine samples etc., through medical examination, or by other known assessments.

[104] A “therapeutic effect” also may include an “additional” therapeutic effect, wherein additional means in addition to the primary effects sought, such as for treatment of the SUD for which the administration is directed. Such additional therapeutic effects include antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, consciousness expanding, consciousness heightening, immunostimulant, anti-cancer, antiemetic, orexigenic, oneirogenic, WO 2025 / 160483                                   PCT / US2025 / 013057 antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, entheogenic, entactogenic or empathogenic, psychedelic, sedative, and stimulant effects.

[105] In embodiments, the additional active agent is selected to provide synergy or a synergistic effect. “Synergy” or a “synergistic effect” include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects), that are greater than the additive contributions of the components (e.g., compounds) acting alone. A synergistic effect may, as an example, enable treatment using lower amounts (doses) of one or more compounds, including of only one compound in a combination (“apparent one-way synergy”), or of two or more compounds in a combination (e.g., “two-way synergy”), than would normally be required when each compound is used alone. Lower doses may result in lower toxicity without reduced efficacy. A synergistic effect also may result in improved efficacy.

[106] Numerous methods will be known to those of skill to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1+1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch Exp Pathol Pharmacol. 114:313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin Pharmacokinet. 6:429-453) and the median-effect equation (Chou &Talalay, 1984, Adv Enzyme Regul. 22:2755). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing synergistic effects.

[107] In embodiments, the additional active agent is selected to provide an additional therapeutic effect, such as antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, entactogenic, empathogenic, entheogenic, euphoric, psychedelic, sedative, and stimulant effects.

[108] In embodiments, the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, antineuropathic agent, antinociceptive agent, antimigraine agent, anxiolytic, antidepressant, antipsychotic, or anti-PTSD agent. In embodiments, the additional active agent is a cannabinoid, dissociative, immunostimulant, anti-cancer agent, chemotherapeutic, antiemetic, hormone, orexigenic, oneirogenic, or antiulcer agent. In embodiments, the additional active agent is an antihistamine, antihypertensive, hypotensive, vasopressor, anticonvulsant, antiepileptic, bronchodilator, neuroprotectant, or neuro-muscle blocker. In embodiments, the additional active agent is an entactogen, empathogen, entheogen, psychedelic, plasticityinducing agent, psychoplastogen, or neuroplastogen. In embodiments, the additional active agent is a monoamine oxidase inhibitor (MAOI), reversible inhibitors of monoamine oxidase-A (RIMA), terpene, tryptamine, or phenethylamine. In embodiments, the additional active agent is a sedative, hypnotic, narcotic, WO 2025 / 160483                                   PCT / US2025 / 013057 serotonergic agent (such as an SSRI, SNRI, NRI, NDRI, or TCA), stimulant, analeptic, psychoneurotropic, antispasmodic, or antiallergic. In embodiments, the additional active agent is a cardiotonic, antiarrhythmic, diuretic, antitussive, antidiabetic, antitumor agent, or vitamin.

[109] In embodiments, the additional active agent is an NMDA modulator, such as disclosed herein.

[110] In embodiments, the additional active agent is an NMDA antagonist, such as disclosed herein.

[111] NMDA modulators, NMDA antagonists, and agents of other disclosed classes herein will be readily known to one of skill, and can be found, for example, on DrugBank (https: / / go.drugbank.com).

[112] In embodiments, the additional active agent is a serotonergic agent. A “serotonergic agent” includes compounds that bind to, block, or otherwise influence (e.g., via an allosteric reaction) activity at one or more serotonin receptors, including any one or more serotonin receptor subtypes. In embodiments, the serotonergic agent is not a psychedelic, or a compound with psychedelic effects. In embodiments, the serotonergic agent binds to a serotonin receptor. In embodiments, the serotonergic agent indirectly affects a serotonin receptor. In embodiments, the serotonergic agent is an agonist. In embodiments, a serotonergic agent is an antagonist. In embodiments, the serotonergic agent is an effector molecule, such as an allosteric regulator. In embodiments, the serotonergic agent acts (either directly or indirectly) at more than one type of receptor, including receptors other than serotonergic or other monoaminergic receptors. In embodiments, the serotonergic agent blocks the serotonin transporter (SERT). In embodiments, the serotonergic agent is a reuptake modulator. In embodiments, the serotonergic agent inhibits the activity of one or both monoamine oxidase enzymes. In embodiments, the serotonergic agent is an antidepressant or anxiolytic, such as an SSRI, serotoninnorepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MA0I), or atypical antidepressant. In embodiments, the serotonergic agent any of a serotonin transport inhibitor, serotonin receptor modulators, serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, serotonin dopamine antagonist, monoamine reuptake inhibitor, pyridazinone aldose reductase inhibitor, stimulant of serotonin receptors, stimulant of serotonin synthesis, serotonin receptor agonist, serotonin receptor antagonist, and serotonin metabolite.

[113] In embodiments, the additional active agent is an opioid antagonist or opioid receptor modulator (e.g., nalmefene, naltrexone, buprenorphine, methadone), a CRH1 receptor antagonist (e.g., verucerfont, pexacerfont), a NK1R antagonist (e.g., tradipitant), an OTR agonist (e.g., oxytocin), a GABAergic agent (e.g., topiramate, baclofen, acamprosate, a benzodiazepine, such as alprazolam, diazepam or lorazepam), a voltagegated sodium channel inhibitor (e.g., oxacarbazepine, valproic acid, zonisamide), a voltage-dependent calcium channel agonist (e.g., gabapentin, pregabalin), an a7 nicotinic acetylcholine receptor agonist (e.g., varenicline), a 5-HT3 antagonist (e.g., ondansetron), a 5-HT1A receptor partial agonist (e.g., aripiprazole), a 5-HT2A receptor antagonist (e.g., quetiapine, olanzapine, mirtazapine), a 5-HT reuptake inhibitor (e.g., trazodone), a SERT inhibitor (e.g., duloxetine), an a1 adrenoreceptor antagonist (e.g., doxazosin, prazosin), a glucocorticoid receptor antagonist (e.g., mifepristone), an a1 adrenoreceptor agonist (e.g., guanfacine), an AChE inhibitor WO 2025 / 160483                                   PCT / US2025 / 013057 (e.g., citicoline), a dopamine agonist, a dopamine D2 receptor antagonist (e.g., tiapride), an a2 adrenoreceptor agonist (e.g., clonidine), an NMDA receptor antagonist (e.g., memantine, acamprosate), and an aldehyde dehydrogenase inhibitor (e.g., disulfiram), an orexin receptor antagonist, a CB1 antagonist (e.g., rimonabant), or an endocannabinoid system modulator.

[114] In embodiments, the additional active agent is a phenethylamine, such as disclosed in Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transf. Press (1994), or a tryptamine, such as disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transf. Press (1997), both incorporated by reference in their entirety.

[115] In embodiments, the additional active agent is ibogaine, kratom, or a natural plant alkaloid.

[116] In embodiments, the additional active agent is an agent useful in the treatment of an SUD, such as an agent approved to treat an SUD, used off-label to treat an SUD, or shown to be efficacious in clinical studies.

[117] Any disclosed additional active agent may be substituted by its ion, free base, salt, hydrate, solvate form, co-crystal, crystalline polymorph, amorphous form, tautomer, structural isomer, stereoisomer, enantiomerically enriched mixture, isotopologue, deuterated variant, prodrug, active metabolite, derivative, or analog, including all combinations of any of the foregoing, and may be in pure or substantially pure form. D. Pharmaceutical Compositions

[118] In some aspects are provided compositions comprising ketamine or esketamine, such as formulated for oral transmucosal administration, including oral thin films (OTFs) comprising ketamine or esketamine.

[119] A “pharmaceutical composition” (or simply, a “composition”) comprises a disclosed compound and one or more (preferably, pharmaceutically acceptable) carriers, diluents, and / or excipients.

[120] A “pharmaceutically acceptable” carrier, diluent, excipient, or other ingredient means the ingredient is generally safe and, within the scope of medical judgment, suitable for use in humans or animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[121] A composition can be prepared by standard formulation techniques such as disclosed in, e.g., Remington: Science & Practice of Pharmacy. 23rd ed. Cambridge, MA: Acad Press (2020); Budavari et al. Merck Index. 12th ed. Whitehouse, NJ: Merck Pub Group (1996); Carstensen. Pharm Principles of Solid Dosage Forms. Lancaster, PA: Technomic Pub Co. (1993); Ansel & Stoklosa. Pharm Calculations. 11th ed. Baltimore, MD: LWW (2001); Poznansky & Cleland. Drug Delivery Systems. NY: Oxford Univ Press (1980).

[122] A composition may be formulated in a unit dosage form, each containing a therapeutically effective amount of the disclosed compound (also, “API” or “active agent”), for example, in disclosed dosage amounts, or a portion (preferably, a defined fraction) of a therapeutically effective amount, e.g., 1 / 2,½, or 1 / 4.

[123] Reference to “a” compound or “an” active agent, in embodiments, includes or refers to more than one compound or active agent, and should be understood as “one or more” unless context demands otherwise.

[124] In embodiments, a composition is formulated for oral transmucosal administration, such as buccal administration and / or sublingual administration (“an oral transmucosal dosage form”).

[125] “Oral transmucosal” administration or delivery refers generally to the application of a pharmaceutically active agent (such as in, and by application of, a pharmaceutical composition) to or in relation to one or more mucosal membranes of the oral cavity, including the cheek, lips, gums, palate, and tongue, thereby permitting or resulting in the passage of the active agent through such membranes into the bloodstream. “Oral transmucosal” may be used interchangeably with “oral mucosal” and “oromucosal.” This includes both “buccal” and “sublingual” administration and delivery. Formulation of an active agent, suitable for oral transmucosal administration, including buccal and sublingual administration, will be known to those of skill in view of the disclosure and the general knowledge in the art; certain such formulations are described herein.

[126] Exemplary oral transmucosal dosage forms include tablets, films, lozenges, gums, sprays, gels, creams, ointments, powders, granules, patches, strips, sachets, pouches, oral solutions, and suspensions.

[127] In embodiments, the oral transmucosal dosage form is a tablet, such as a rapid disintegrating tablet, an orally disintegrating tablet (ODT), an effervescent tablet, a mucoadhesive tablet, a buccal tablet, or a sublingual tablet. In embodiments, the oral transmucosal dosage form is a film, such as an oral thin film (OTF), a fast-dissolving film (FDDF), or a mucoadhesive film. In embodiments, the oral transmucosal dosage form is a lozenge or related form, such as a lozenge, a troche, a pastille, or a lollipop. In embodiments, the oral transmucosal dosage form is a gum, such as a chewing gum or a medicated gum. In embodiments, the oral transmucosal dosage form is a spray, such as a sublingual spray or a buccal spray. In embodiments, the oral transmucosal dosage form is a gel, cream, or ointment. In embodiments, the oral transmucosal dosage form is a powder or granule for oral application. In embodiments, the oral transmucosal dosage form is a patch, such as attached with an adhesive to a mucosal surface in the oral cavity, such as a buccal patch or a sublingual patch. In embodiments, the oral transmucosal dosage form is a strip, such as a dissolvable strip, a sachet, or a pouch. In embodiments, the oral transmucosal dosage form is an oral solution or suspension.

[128] In embodiments, the oral transmucosal dosage form is a “closed” delivery system, wherein the drug delivery conditions are primarily governed by the formulation itself, including the environmental conditions within the dosage form. In embodiments, the closed delivery system facilitates drug delivery through the use of enhancers or permeability facilitators. In embodiments, the closed delivery system is a patch, such as a buccal patch. In embodiments, drug delivery via a patch, such as a buccal patch, exhibits a pharmacokinetic (PK) profile similar to that of a short-term intravenous (IV) infusion.

[129] In embodiments, the oral transmucosal dosage form is an “open” delivery system, wherein the drug delivery conditions are influenced by external environmental factors, such as the rate of saliva secretion, the pH of the saliva, or other conditions beyond the formulation itself. In embodiments, the open delivery system is a lozenge or a sublingual tablet.

[130] In embodiments, the oral transmucosal dosage form is an oral thin film (OTF).

[131] Without being bound by theory, an “oral thin film” (“OTF”) is a thin, polymer-based film that comprises at least one active agent and, when applied to a mucous membrane, such as the oral mucosa of a subject, such as a human, delivers or is capable of delivering the active agent through the mucous membrane and into WO 2025 / 160483                                   PCT / US2025 / 013057 the bloodstream. An OTF may be placed directly in the oral cavity or against the oral mucosa, may dissolve or macerate there (or be capable thereof), and in so doing deliver the active agent. The active agent(s) may be, for example, dissolved, emulsified, or dispersed in the film.

[132] Exemplary OTF formulations will be known to those of skill in view of the disclosure.

[133] In embodiments, the OTF comprises a hydrophilic or hydrophobic polymer matrix as a primary structural component. Suitable hydrophilic polymers include pullulan, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), sodium alginate, and maltodextrin. Suitable hydrophobic polymers include ethyl cellulose and Eudragit. The OTF may further comprise plasticizers, such as glycerin or polyethylene glycol (PEG), to enhance flexibility and handling properties. The OTF may comprise additional non-polymeric excipients, such as flavoring agents, taste-masking agents, and surfactants, for example to improve patient compliance or drug delivery performance. In embodiments, the OTF is designed for rapid dissolution and absorption, releasing a substantial portion of the active agent within minutes of administration.

[134] In embodiments, an OTF offers one or more advantages for drug delivery. For example, the high blood supply to the oral mucosa can facilitate rapid transfer of the active agent into the bloodstream. OTFs moreover may enable the active agent to be predominantly absorbed through the mucous membrane, which can help avoid the first-pass effect commonly associated with conventional dosage forms, such as tablets.

[135] The active agent may be dissolved, emulsified, or dispersed within the disclosed OTF. Without being bound by theory, esketamine delivery from an OTF may occur through two pathways: a direct pathway, where esketamine is absorbed from the OTF into the bloodstream, and an indirect pathway, where a portion of esketamine dissolves in saliva, is ingested, and subsequently absorbed in the gastrointestinal tract.

[136] In embodiments, an OTF is designed to minimize drug delivery through the indirect pathway. For example, the OTF may be formulated to achieve a direct-to-indirect delivery ratio that favors direct delivery, such as a ratio of at least 2:1, 5:1, 10:1, or greater than 10:1. In embodiments, the ratio of direct to indirect delivery is optimized by modifying the composition, thickness, or dissolution properties of the OTF to enhance absorption through the mucous membrane while limiting dissolution in saliva. In embodiments, an OTF comprises one or more excipients, permeation enhancers, or mucoadhesive agents to promote direct delivery and reduce the amount of active agent available for indirect absorption through the gastrointestinal tract.

[137] In embodiments, the OTF is an oral thin film described in any of PCT Pub. Nos. WO2023 / 094638, WO2022 / 207257, WO2022 / 184770, WO2022 / 152877, WO2022 / 152874, WO2022 / 152878, WO2022 / 152883, WO2022 / 096676, WO2021 / 001461, WO2019 / 207067, or WO2019 / 110727, all of which are incorporated by reference as if fully set forth herein, or claimed by any issued patent descended therefrom. Examples of oral thin films described therein include those manufactured by LTS Lohmann Therapie-Systeme AG (Andernach, Germany) (“LTS”) (all together, an “LTS OTF”). In embodiments, the OTF is an oral thin film disclosed in WO2022 / 096676 or an oral thin film claimed in U.S. Patent No. 11,992,561, the complete contents of which are incorporated by reference as if fully set forth herein, or as otherwise manufactured by LTS. WO 2025 / 160483                                   PCT / US2025 / 013057

[138] In some embodiments, the oral thin film is an OTF described in PCT Pub. No. WO2022 / 096676.

[139] In some embodiments, the oral thin film is an OTF claimed in U.S. Patent No. 11,992,561.

[140] In embodiments, and without being limited by any such characterization, an LTS OTF comprises at least one matrix layer, wherein the at least one matrix layer comprises at least one pharmaceutically active agent, at least one polyvinyl alcohol, and at least one polyvinyl alcohol-polyethylene glycol graft copolymer.

[141] In embodiments, the at least one pharmaceutically active agent is ketamine or esketamine.

[142] In embodiments, the OTF is provided in the form of a single-layer film, consisting of a single matrix layer. In embodiments, the OTF is provided in the form of a multi-layer film, comprising additional layers beyond the matrix layer. Additional layers may include buffer layers for pH adjustment, slowly dissolving layers, or insoluble layers. Additional matrix layers may incorporate other pharmaceutically active agents, flavorings, or taste-masking agents. In embodiments, the OTF is characterized by a high active agent load, a soft texture, and stability, and it can be designed to release a substantial amount (e.g., up to 90%) of the contained active agent(s) within minutes of administration.

[143] In embodiments, the oral transmucosal dosage form is a fast-dissolving dosage form (FDDF).

[144] Exemplary FDDFs include loosely compressed tablets comprising a relatively large amount of wicking or disintegrating agents, tablets comprising a relatively large amount of effervescent agents, lyophilized tablets, and dosage forms using rapidly soluble gelatin-based matrices, or using gelatin or mannitol as carriers or matrix forming agents, and which are designed to release the active ingredient in the oral cavity (Seager. J Pharm Pharmacol. 1998;50(4):375-382).

[145] In embodiments, the FDDF is a freeze-dried oral solid dosage form, such as an orally dissolving tablet (ODT). In embodiments, the ODT is a ZYDIS® oral solid dosage form, including a ZYDIS ODT, such as ZYDIS Ultra (Catalent, Swindon, U.K.). In embodiments, the ODT is a ZYDIS ODT such as described in U.S. Patent No. 9,192,580, which is incorporated by reference as if fully set forth herein. In embodiments, the ODT comprises an active agent, such as esketamine, a non-gelling matrix former, a filler, a binder, and a pH modifying agent (i.e., a buffer), and optionally any one or more of antioxidants, photostabilization agents, permeation enhancers, coloring agents, sweeteners, and flavorants or flavoring agents.

[146] In embodiments, WO2023 / 23182 or WO2023 / 23192, incorporated by reference, describe the ODT. E. Methods of Treatment

[147] In some aspects are provided methods of using a disclosed composition to treat an SUD.

[148] In embodiments, compositions are administered to treat an SUD, according to disclosed methods.

[149] In embodiments, compositions are administered to treat an SUD, in combination with psychotherapy.

[150] “Treat” including its various conjugations refers herein to treating a disease or disorder in a human or other mammal, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e. arresting its development; (c) relieving a disorder, i.e., causing its regression; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. In embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the disclosure and the art.

[151] Treatment, generally, will be of a mammal, and in particular a human, who may be referred to interchangeably, unless context demands otherwise, as a “subject,” “patient,” or “individual.” In some examples, the term “participant” also may be used. A subject includes one who has an indication for which disclosed composition or method may be efficacious, or who otherwise may benefit therefrom. In general, all of the disclosed compositions and methods should be appreciated to work for all subjects, although a degree of individual variation is to be expected, and will be understood. In embodiments, a subject includes one who has an SUD, or another condition for which the disclosed treatments may be efficacious. A subject may include one in need of treatment for a disorder, or one predisposed to a disorder. A subject also may include one who is diagnosed with a disorder, such as an SUD, as well as one who is not diagnosed with a disorder.

[152] Certain subjects may receive particular benefit from disclosed methods. In embodiments, a subject is a veteran of the armed services, a member of the armed services, or a current or retired first responder, such as a law enforcement officer, a firefighter, or emergency medical personnel, such as a paramedic or an EMT.

[153] In embodiments, the method comprises selecting the subject on the basis of one or more predefined inclusion or exclusion criteria (e.g., based on a pre-assessment eligibility check). In embodiments, the method comprises a pre-treatment assessment of the subject. In embodiments, the method comprises a post-treatment assessment of the subject.

[154] A “substance use disorder” or “SUD” refers to a medical condition broadly defined by the inability to control the use of a particular substance despite harmful consequences. SUDs may be characterized by excessive use of nicotine, alcohol, and narcotics including prescription drugs and illicit drugs, where such use leads to one or more of social, academic, and occupational impairment. SUDs include disorders relating to the use of alcohol, tobacco (nicotine), cannabis, sedatives, hypnotics, anxiolytics, inhalants, opiates, opioids, and stimulants (Jahan & Burgess. SUDs. Treasure Island (FL): StatPearls Publishing; 2022), among others.

[155] In embodiments, the SUD is alcohol use disorder (AUD), opioid use disorder (OUD), nicotine dependence or tobacco use disorder, sedative, hypnotic, and anxiolytic use disorder or stimulant use disorder.

[156] The determination of whether a subject has an SUD, such as any SUD disclosed herein, can be determined according to ordinary skill, such as based on the definitions in the 11th Revision of the International Classification of Diseases (ICD-11), based on the definitions in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), or based on the Merck Manual of Diagnosis & Therapy, 20th Ed. (2018) (“Merck WO 2025 / 160483                                   PCT / US2025 / 013057 Manual”). The determination of whether a subject has another disorder, such as a behavioral addiction or a mental health disorder, can be likewise determined according to ordinary skill.

[157] The severity of a disorder (e.g., mild, moderate, severe) can be likewise determined by one of skill.

[158] In embodiments, the SUD is a comorbidity in a subject with another disorder or condition, such as a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the SUD is a comorbidity in a subject who also has another SUD (i.e., is separate from the “primary” SUD being treated). In embodiments, the SUD is not a comorbidity in a subject with another diagnosed or diagnosable condition.

[159] A “mental health disorder” refers to a disease condition in a human that involves negative changes in emotion, mood, thinking, or behavior, and that generally causes distress or impairment of personal functioning (Bolton. J Merit Health. 2010;19(4):328-336). Mental health disorders include post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorders due to medical conditions, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, mood disorders related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, dissociative disorders, and substance-related disorders, including alcohol or drug abuse or dependence disorders (see Merck Manual of Diagnosis & Therapy, 20th Ed. (2018)).

[160] A “neurodegenerative disorder” is any of Alzheimer’s disease, amyotrophic lateral sclerosis, Charcot’s disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease, Parkinsonisms, prion disease, progressive supranuclear palsy, and traumatic brain injury (TBI), including mild traumatic brain injury (mTBI).

[161] In embodiments, a disclosed method results in any one or more of: (a) a reduction of substance use; (b) a reduction of substance cravings; (c) a promotion of abstinence from substance use; (d) a prevention of relapse into substance use; and (e) an improvement of at least one symptom of an SUD, or a reduction in the severity of at least one diagnostic criterion for the SUD.

[162] In embodiments, reducing substance use ora reduction of substance use refers to reducing the amount or frequency of substance use. In embodiments, reducing substance use refers to a reduction in an amount of substance use per day or a reduction in the frequency of substance use, such as a reduction in the percentage of substance use days or a percentage of heavy substance use days. In embodiments, reducing substance use refers to an increase in the time between consuming at least the substance, such that less total units of the substance are consumed within a given timeframe.

[163] “Abstinence from a substance” refers to the cessation of substance consumption for an extended period of time, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more. The term “promoting abstinence from a substance” or “promotion of abstinence from substance use” refers to helping to maintain abstinence from substance use, in particular after at least 1 day of not using the substance of abuse, for example maintaining abstinence from substance use for a period of days, including a period of a week or more, including more than one week, more than two weeks, more than three weeks, and a month or more, including more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, and a year or more, including more than 1 year, more than 2 years, more than 3 years, more than 4 years, and more than 5 years, including values in between. In embodiments, “promoting substance use abstinence” refers to maintaining abstinence from substance use, in particular, after at least 1 day of not using the substance, for example maintaining abstinence from substance use for at least 3 months, 6 months, or 9 months, or for more than 9 months, including for more than 1 year, more than 2 years, and more than 3 years.

[164] “Relapse into substance use” refers to substance intake (i.e., the consumption of a substance of abuse or the “taking” of said substance) following a period of abstinence from the substance, for example following a period of abstinence of at least 1 day or more, such as 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 9 months, 1 year, or greater than 1 year, and values in between. In embodiments, preventing relapse into substance use refers to the prevention of substance intake by a subject after the subject has ceased the intake of the substance for at least 24 hours. In embodiments, preventing relapse into substance use refers to the prevention of substance intake by a subject after the subject has ceased the intake of the substance for less than 24 hours. In embodiments, preventing relapse into substance use refers to the permanent cessation of consuming that substance. In embodiments, preventing relapse into substance use refers to an increase in time prior to the resumption of substance intake as compared to the time prior to the resumption of substance intake by a subject not treated according to a disclosed method. In embodiments, the increase in time prior to the resumption can be, e.g., at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or a week or more, including more than 1 week, more than 2 weeks, more than 3 weeks, and a month or more, including more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, and a year or more, including more than 1 year, more than 2 years, more than 3 years, more than 4 years, and more than 5 years, including values in between. a. Alcohol Use Disorder (A UD)

[165] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s alcohol intake. In embodiments, the subject has alcohol use disorder (AUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of AUD. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat AUD. In embodiments, the AUD is alcohol abuse, alcohol dependence, or alcoholism. In embodiments, the AUD may be “harmful use” and / or “dependent use” AUD. WO 2025 / 160483                                   PCT / US2025 / 013057

[166] In embodiments, the subject reduces or abstains from alcohol use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[167] In embodiments, a method comprises administering a composition to a subject with AUD to treat the AUD. In embodiments, the method thereby treats the AUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat AUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat AUD. In embodiments, a subject is administered an esketamine OTF to treat AUD.

[168] In embodiments, “alcohol use disorder” (AUD) refers to the disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, for example, the DSM-5. Under the DSM-5, meeting any two of 11 listed criteria during the same 12 month period can produce a diagnosis of AUD. AUD thus may refer to the disorder defined in the DSM-5. The severity of AUD as mild, moderate, or severe is based on the number of criteria met. The criteria being, whether in the past year, a subject has: (1) Had times when you [i.e., the subject] ended up drinking more, or longer, than you intended? (2) More than once wanted to cut down or stop drinking, or tried to, but couldn’t? (3) Spent a lot of time drinking? Or being sick or getting over other aftereffects? (4) Wanted a drink so badly you couldn’t think of anything else? (5) Found that drinking—or being sick from drinking—often interfered with taking care of your home or family? Or caused job troubles? Or school problems? (6) Continued to drink even though it was causing trouble with your family or friends? (7) Given up or cut back on activities that were important or interesting to you, or gave you pleasure, in order to drink? (8) More than once gotten into situations while or after drinking that increased your chances of getting hurt (such as driving, swimming, using machinery, walking in a dangerous area, or having unsafe sex)? (9) Continued to drink even though it was making you feel depressed or anxious or adding to another health problem? Or after having had a memory blackout? (10) Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before? (11) Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, restlessness, nausea, sweating, a racing heart, or a seizure? Or sensed things that were not there? The severity of AUD—mild, moderate, or severe—is based on the number of criteria met. For instance, in the 2015 National Survey on Drug Use and Health survey, wherein 43,561 individuals were polled, 11.8% met the criteria for alcohol use disorder—67% of which were “mild” cases (2-3 symptoms), 18.8% had a moderate disorder (4-5 symptoms), and 13.8% possessed a severe disorder (6 or more symptoms) (Witkiewitz et al. SciAdv. 2019;5(9):eaax4043).

[169] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[170] In embodiments, treatment with a composition, either alone or with psychotherapy, treats AUD.

[171] Although herein the terms “alcohol use disorder” and “AUD” generally refer to the DSM-5 criteria, or a subject with a diagnosis based thereon, it will be appreciated that the disclosed compositions and methods (for AUD, and for all other disorders discussed herein) are equally applicable to subjects having the equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in DSM-5 or in DSM-IV (which described two distinct disorders: “alcohol abuse” and “alcohol dependence” each with specific criteria), whether the diagnosis is based on other clinically acceptable criteria (e.g., as “Alcohol Dependence Syndrome,” see Edwards. Brit. J. Addiction. 1986;81:171-183), or whether the subject has not yet had a formal clinical diagnosis.

[172] In embodiments, AUD refers to a problematic pattern of alcohol use accompanied by clinically significant impairment or distress (Kranzler et al. JAMA. 2018;320(8):815-824). In embodiments, AUD refers to a disease characterized by a loss of control over alcohol drinking accompanied by changes in brain regions related to the execution of motivated behaviors and to the control of stress and emotionality (e.g., the midbrain, the limbic system, the prefrontal cortex, and the amygdala) (Witkiewitz 2019).

[173] “Alcohol dependence” refers to the more severe form of AUD involving physical alcohol dependence. Use of terms such as “physically dependent” alcoholism, “physically dependent” alcohol addiction, or “physically dependent” AUD, therefore will be understood to refer to the psychiatric disorder or condition in which an individual has become physically dependent upon, or physically addicted to, alcohol (e.g., “Alcohol Dependence Syndrome”). Typically alcohol dependence is characterized by (often serious) withdrawal symptoms on cessation of alcohol, or drinking to avoid withdrawal symptoms, tolerance and the persistent desire to drink, and continuing drinking despite negative consequences (NICE. Alcohol use disorders. The British Psychological Society & The Royal College of Psychiatrists; 2013 (“The NICE Guidelines”)).

[174] “Harmful use of alcohol” or “harmful use” AUD refers to the definition in the WHO’s International Classification of Diseases, 10th Revision (ICD-10 Classification of Mental and Behavioral Disorders). AUD subjects characterized as “harmful use,” refer to those engaging in “harmful alcohol use,” characterized by a pattern of use that causes damage to health, either physical or mental, and which has adverse social consequences, including affecting personal relationships, professional relationships, familial relationships, etc. (however, adverse social consequences themselves do not justify a diagnosis of “harmful use”).

[175] In embodiments, “harmful use” or “harmful alcohol use” refer to a condition where a subject scores between 0 and 15 on the SADQ. In embodiments, “harmful use” or “harmful alcohol use” refer to a condition where a subject scores between 0 and 15 on the SADQ, and where the subject exhibits at least one of damage to health (e.g., physical, mental, or physical and mental health), and strained / damaged social relationships.

[176] The distinction between the different severities of AUD can vary over time within a single subject’s relationship with alcohol; however, one of skill will appreciate how an appropriate and reasonable clinical determination is made. Clinical signs and tools used to distinguish between those AUD subjects with nonphysical “harmful use” and those who are physically dependent on alcohol include whether or not there is evidence of physical dependence (including evidence of severe sweating, tremor, vomiting, nausea, or confusion on cessation of drinking for >48 hours); whether or not there is evidence of a strong craving to drink alcohol in order to combat the symptoms of alcohol withdrawal; and whether one scores 15 or less (non dependent, harmful use) or greater than 15 (dependent) on the Severity of Alcohol Dependence Questionnaire (SADQ). The NICE Guidelines explain: “Although alcohol dependence is defined in ICD-10 and DSM-IV in categorical terms for diagnostic and statistical purposes as being either present or absent, in reality, dependence exists on a continuum of severity. Therefore, it is helpful from a clinical perspective to subdivide dependence into categories of mild, moderate, and severe. People with mild dependence (e.g., those scoring 15 or less on the Severity of Alcohol Dependence Questionnaire; SADQ) usually do not need assisted alcohol withdrawal. People with moderate dependence (with a SADQ score of between 15 and 30) usually need assisted alcohol withdrawal, which can typically be managed in a community setting unless there are other risks. People who are severely alcohol dependent (with a SADQ score of 30 or more) will need assisted alcohol withdrawal, typically in an inpatient or residential setting. In this guideline these definitions of severity are used to guide selection of appropriate interventions.”

[177] In embodiments, the categories of mild, moderate, and severe may be diagnosed based on the symptoms as defined by the DSM-5, wherein “mild” refers to two or three symptoms, “moderate” refers to four or five symptoms, and “severe” refers to six or more symptoms.

[178] “Binge drinking” refers to a pattern of drinking that brings a person’s blood alcohol concentration (BAG) to at least .08 g / dL. A “binge drinker,” i.e., one who binge drinks, is referred to as an “alcohol abuser” or “abuser of alcohol,” wherein the act of binge drinking itself may be referred to as “alcohol abuse” or “abuse of alcohol.” Abusers of alcohol may not drink on a consistent basis; for example, they may only drink once a week, but, when drinking, they may drink heavily, which may cause adverse health effects, such as, but not limited to, suffering from alcohol intoxication; unintentional injuries, such as car accidents, falls, burns, and alcohol poisoning; violence, including homicide, suicide, domestic violence, and sexual assault; sexually transmitted diseases; unintended pregnancy and poor pregnancy outcomes, including miscarriage and stillbirth, fetal alcohol spectrum disorders, and sudden infant death syndrome; chronic diseases such as, but not limited to, high blood pressure, stroke heart disease, and liver disease; cancer, including but not limited to breast cancer, mouth cancer, throat cancer, esophageal cancer, liver cancer, and colon cancer; memory and learning problems; and other behavioral addictions and substance use disorders (GDC, 2019).

[179] The frequency at which one binge drinks may determine whether or not the individual is considered a “heavy drinker” or “heavy alcohol user.” “Heavy drinker” refers to someone with a heavy alcohol use pattern. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Substance Abuse and Mental Health Services Administration (SAMHSA) define “heavy alcohol use” as binge drinking on 5 or more days in the past month. NIAAA defines binge drinking as a pattern of drinking that brings BAG levels to at least 0.08 g / dL. This typically occurs after 4 alcoholic drinks for women and 5 alcoholic drinks for men within a period of about 2 hours. SAMHSA defines “binge drinking” as 5 or more alcoholic drinks for males or 4 or more alcoholic drinks for females on the same occasion on at least 1 day in the past month.

[180] “Alcohol craving” refers to a conscious desire or urge to consume alcohol.

[181] “Reducing alcohol use” refers to reducing the amount or frequency of alcohol use, and may be assessed by urinalysis (e.g., measuring metabolites of alcohol in urine, such as Ethyl Glucuronide (EtG)) or by self-reporting with standardized tools, such as the Timeline Follow-Back self-report (Sobell & Sobell. Problem drinkers: Guided self-change treatment. The Guilford Press; 1996). In embodiments, a “reduction of alcohol use” refers to a reduction in drinks per day, a reduction in drinks per drinking day, or a reduction in the frequency of drinking, such as a reduction in the percentage of drinking days or percentage of heavy drinking days. In embodiments, a “reduction of alcohol use” refers to an increase in the time between consuming at least one drink of alcohol, such that less total units of alcohol are consumed within a given timeframe.

[182] A “unit of alcohol” refers to a standard drink, which contains about 12-14 g of pure alcohol (ethanol), such as 12 ounces of 5% alcoholic beer, 5 ounces of 12% alcoholic wine, or 1.5 ounces of 40% spirits (NIH).

[183] A “heavy drinking day” refers to a day with a total alcohol consumption >60 g of ethanol for men and >40 g for women. In embodiments, a “reduction of alcohol use” refers to increasing the period of time of a “heavy drinking day,” wherein a “heavy drinking day” refers to a given 24-hour period in which the pattern of drinking meets that of “binge drinking,” as defined herein.

[184] “Alcohol abstinence” or “abstinence from alcohol” refers to the cessation of alcohol consumption for an extended period of time, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more. The term “promoting alcohol abstinence” or “promotion of alcohol abstinence” refers to helping to maintain abstinence from alcohol use, in particular after at least 1 day of not drinking alcohol, for example maintaining abstinence from alcohol use for a period of days, including a period of a week or more, including more than one week, more than two weeks, more than three weeks, and a month or more, including more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, and a year or more, including more than 1 year, more than 2 years, more than 3 years, more than 4 years, and more than 5 years, including values in between. In embodiments, “promoting alcohol abstinence” or “promotion of alcohol abstinence” refers to helping to maintain abstinence from alcohol use, in particular after at least 1 day of not drinking alcohol, for example maintaining abstinence from alcohol use for for at least 3 months, 6 months, or 9 months, or for more than 9 months, including for more than 1 year, more than 2 years, and more than 3 years.

[185] “Relapse into alcohol use” or “relapse into alcohol consumption” refers to alcohol intake (i.e., the consumption of alcohol or the “taking” of alcohol) following a period of alcohol abstinence, for example following a period of alcohol abstinence of at least 1 day or more, such as 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 9 months, 1 year, or greater than 1 year, and values in between. In embodiments, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to the prevention of alcohol intake by an AUD subject after the subject has ceased the intake of alcohol for at least 24 hours. In embodiments, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to WO 2025 / 160483                                   PCT / US2025 / 013057 the prevention of alcohol intake by an AUD subject after the subject has ceased the intake of alcohol for less than 24 hours. In embodiments, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to the permanent cessation of alcohol intake.

[186] In embodiments, wherein a subject is treated according to a disclosed method, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to an increase in time prior to the resumption of alcohol intake as compared to the time prior to the resumption of alcohol intake by a subject who is not treated according to the method. In embodiments, the increase in time prior to the resumption can be, e.g., at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or a week or more, including more than one week, more than two weeks, more than three weeks, and a month or more, including more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, and a year or more, including more than 1 year, more than 2 years, more than 3 years, more than 4 years, and more than 5 years, including values in between.

[187] “AUD associated with high risk drinking for acute problems” refers to AUD associated with daily alcohol consumption >60 g / day (76.05 mL / day) of ethanol for men and >40 g / day (50.7 mL / day) for women (Int’l Guide for Monitoring Alcohol Consumption and Related Harm, WHO / MSD / MSB / 00.4; WHO 2000, p. 51).

[188] In some embodiments, treating AUD comprises reducing any one or more of a subject’s alcohol intake, a subject’s alcohol cravings, and a subject’s cue reactivity to alcohol-related stimuli. A reduction in alcohol use refers to reducing the amount or frequency of alcohol use, for example as assessed by urinalysis e.g., by measuring metabolites of alcohol in urine, such as ethyl glucuronide (EtG) or as assessed by using self-reported alcohol use with standardized tools like the Timeline Follow Back self-report. Cravings, including reductions thereof, may be determined using a self-reported scale, e.g., the Penn Alcohol Craving Scale.

[189] In some embodiments, reducing alcohol use or reduction of alcohol use refers to a reduction in drinks per day, a reduction in drinks per drinking day, or a reduction in the frequency of drinking, such as a reduction in the percentage of drinking days or percentage of heavy drinking days. In certain embodiments, a reduction in alcohol consumption is a reduction in the number of heavy drinking days. In some embodiments, reducing alcohol use or reduction of alcohol use refers to an increase in the time to drinking or the time to the first heavy drinking day. “Drinks” or “alcoholic drinks” as used herein, is understood in the context of “standard drinks such as spirits or blends that are intended for human consumption, wherein a “standard drink” equals 12 g ethanol.

[190] In embodiments, a subject is administered an additional active agent, such as a composition comprising the additional active agent, where the additional active agent is a pharmacological agent for AUD.

[191] In embodiments, the pharmacological agent for AUD is acamprosate, disulfiram, naltrexone, or nalmefene. In embodiments, the pharmacological agent for AUD is an opioid antagonist (e.g., nalmefene), CBi antagonist (e.g., rimonabant), CRHi receptor antagonist (e.g., verucerfont, pexacerfont), NKir antagonist (e.g., tradipitant), OTR agonist (e.g., oxytocin), GABA agent (e.g., topiramate, baclofen, benzodiazepines), voltage- gated sodium channel inhibitor (e.g., oxacarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonist (e.g., gabapentin, pregabalin), a? nicotinic acetylcholine receptor agonist (e.g., varenicline), 5-HT3 antagonist (e.g., ondansetron), 5-HTia receptor partial agonist (e.g., aripiprazole), 5-HT2A receptor antagonist (e.g., quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitor (e.g., trazodone), SERT inhibitor (e.g., duloxetine), ai adrenoreceptor antagonist (e.g., doxazosin, prazosin), glucocorticoid receptor antagonist (e.g., mifepristone), ai adrenoreceptor agonist (e.g., guanfacine), AChE inhibitor (e.g., citicoline), dopamine D2 receptor antagonist (e.g., tiapride), or 02 adrenoreceptor agonist (e.g., clonidine).

[192] In embodiments, a subject is administered ketamine or esketamine together with one or more pharmacological agents for AUD. In embodiments, the subject is not being administered a pharmacological agent for AUD, or who has not been administered one, more than one, or any of the above pharmacological agents for a period, such as greater than one day, greater than one week, greater than 1 month, greater than another period of weeks (e.g., greater than 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 10 weeks, or greater than 12 weeks) or greater than another period of months (e.g., greater than 2 months, 3 months, 4 months, 5 months, 6 months, 10 months, or greater than 12 months), including periods of time in between.

[193] In embodiments, the AUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, AUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. b. Cannabis Use Disorder (CUD)

[194] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s cannabis intake. In embodiments, the subject has cannabis use disorder (CUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of cannabis CUD. In some embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat CUD.

[195] In embodiments, the subject reduces or abstains from cannabis use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[196] In embodiments, a method comprises administering a composition to a subject with CUD to treat the CUD. In embodiments, the method thereby treats the CUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat CUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat CUD. In embodiments, a subject is administered an esketamine OTF to treat CUD.

[197] “Cannabis use disorder” (CUD) refers to the disorder as defined, for example, in the DSM-5.

[198] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject. WO 2025 / 160483                                   PCT / US2025 / 013057

[199] In embodiments, treatment with a composition, either alone or with psychotherapy, treats CUD.

[200] In some embodiments, treating CUD comprises reducing any one or more of a subject’s cannabis intake, a subject’s cannabis cravings, and a subject’s cue reactivity to cannabis-related stimuli. A reduction in cannabis use refers to reducing the amountorfrequency of cannabis use, for example as assessed by biological specimen testing, e.g., urinalysis of delta-9-THC metabolites, such as 11 -nor-delta-9-tetrahydro- cannabinol-9-carboxylic acid (9-carboxy-THC), in urine, blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment, e.g., the Severity of Dependence Scale (SDS) (DeGregorio et al., SciRep. 2021 Nov 23;11 (1):22776), Curran et al., Psychol Med. 2019 Jul; 49(9): 1574-1580; Cobo-Golpe et al., J Anal Toxicol. 2021 Nov 9;45(9):969-975). In embodiments, CUD comprises use of one or more compounds or products containing such compound(s) that modulate activity of the cannabinoid 1 (CB1) receptor, such as the main psychoactive compound in cannabis, tetrahydrocannabinol (THC). In embodiments, CUD comprises use of cannabis, one or more natural or synthetic cannabinoids, or combinations thereof. Reductions in cravings and / or cue reactivity may be determined according to methods known to one of skill, e.g., use of an assessment, such as the Marijuana Craving Questionnaire-17 (MCQ17) (see also Norberg et al., Addiction. 2016 Nov;111 (11):1923-1934).

[201] In embodiments, the CUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the CUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. c. Hallucinogen Use Disorder (HUD)

[202] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s hallucinogen intake. Herein, “hallucinogen” and “psychedelic” are used interchangeably. In embodiments, the subject has hallucinogen use disorder (HUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of HUD. In embodiments, the composition, such as the esketamine OTF, is administered to a subject in need thereof to treat HUD.

[203] In embodiments, the subject reduces or abstains from hallucinogen use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[204] In embodiments, a method comprises administering a composition to a subject with HUD to treat the HUD. In embodiments, the method thereby treats the HUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat HUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat HUD. In embodiments, a subject is administered an esketamine OTF to treat HUD.

[205] “Hallucinogen use disorder” (HUD) refers to the disorder as defined, for example, in the DSM-5. WO 2025 / 160483                                   PCT / US2025 / 013057

[206] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[207] In embodiments, treatment with a composition, either alone or with psychotherapy, treats HUD.

[208] In embodiments, treating HUD comprises reducing any one or more of a subject’s hallucinogen intake, a subject’s hallucinogen cravings, and a subject’s cue reactivity to hallucinogen-related stimuli. A reduction in hallucinogen use refers to reducing the amount or frequency of hallucinogen use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment, e.g., the Severity of Dependence Scale (SDS) (see, e.g., Jang et al., JPharm Biomed Anal. 2015 Nov 10; 115:138-43). Reductions in cravings and / or cue reactivity may be determined using methods available to one of skill, e.g., an assessment like the Brief Substance Craving Scale (BCBS).

[209] In embodiments, the HUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the HUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. d. Inhalant Use Disorder (IUD)

[210] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s inhalant intake. In embodiments, the subject has inhalant use disorder (IUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of IUD. In some embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat IUD.

[211] In embodiments, the subject reduces or abstains from inhalant use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[212] In embodiments, a method comprises administering a composition to a subject with IUD to treat the IUD. In embodiments, the method thereby treats the IUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat IUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat IUD. In embodiments, a subject is administered an esketamine OTF to treat IUD.

[213] “Inhalant use disorder” (IUD) refers to the disorder as defined, for example, in the DSM-5.

[214] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[215] In embodiments, treatment with a composition, either alone or with psychotherapy, treats IUD.

[216] In some embodiments, treating IUD comprises reducing any one or more of a subject’s inhalant intake, a subject’s inhalant cravings, and a subject’s cue reactivity to inhalant-related stimuli. A reduction in inhalant use refers to reducing the amount or frequency of inhalant use, for example as assessed by biological specimen testing, e.g., blood analysis, such as detection of elevated liver enzymes, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment, e.g., the Severity of Dependence Scale (SDS). See, e.g., Jain & Verma, J Pharm Bioallied Sci. 2016 Jan-Mar; 8(1): 18-22. Reductions in cravings and / or cue reactivity may be determined according to methods available to one of skill in the art, e.g., use of an assessment, such as the Brief Substance Craving Scale (BCBS), Penn Alcohol Craving Scale - Inhalants (PACS-I), or the inhalant craving questionnaire (ICQ). See, e.g., Alonso-Matias et al., Adicciones. 2015 Dec 15;27(4):276-87, Jain et al., Asian J Psychiatr. 2017 Dec;30:202-207, and Kalaysiri et al., Psychiatry Res. 2018 Mar;261:61-67.

[217] In embodiments, IUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, IUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. e. Opioid Use Disorder (OUD)

[218] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s opioid intake. In embodiments, the subject has opioid use disorder (OUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of OUD. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat OUD.

[219] In embodiments, the subject reduces or abstains from opioid use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[220] In embodiments, a method comprises administering a composition to a subject with OUD to treat the OUD. In embodiments, the method thereby treats the OUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat OUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat OUD. In embodiments, a subject is administered an esketamine OTF to treat OUD.

[221] “Opioid use disorder” (OUD) refers to the disorder as defined, for example, in the DSM-5.

[222] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[223] In embodiments, treatment with a composition, either alone or with psychotherapy, treats OUD.

[224] In embodiments, treating OUD comprises reducing any one or more of a subject’s opioid intake, a subject’s opioid cravings, and a subject’s cue reactivity to opioid-related stimuli. A reduction in opioid use refers to reducing the amount or frequency of opioid use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using an assessment, e.g., the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) and the Severity of Dependence Scale (SDS) (see, e.g., Coyne et al., CurrMed Res Opin. 2021 Mar;37(3):493-503; Kale, Am Fam Physician. 2019 Jan 1 ;99(1):33-39; Madry, Bioanal. 2016 May;8(9):953-64). Reductions in cravings and / or cue reactivity may WO 2025 / 160483                                   PCT / US2025 / 013057 be determined according to methods available to one of skill, e.g., use of an assessment, such as the Brief Substance Craving Scale (BCBS), Visual Analog Scale (VAS), Desires for Drug Questionnaire (DDQ), Heroin Craving Questionnaire (HCQ), and Obsessive-Compulsive Drug Use Scale (OCDUS) (see, e.g., Kleykamp et al., Drug Alcohol Depend. 2019 Dec 1;205:107639).

[225] In embodiments, a disclosed method relieves or avoids the symptoms of opioid withdrawal.

[226] In embodiments, a disclosed method may be used as an adjunct to clinical opioid therapy.

[227] Opioids include hydrocodone, hydromorphone, methadone, meperidine, and oxycodone. “Opioids,” unless context demands otherwise, also include “opiates,” such as codeine, morphine, and heroin.

[228] Conventional treatments for OUD include opioid receptor agonists, e.g., methadone and buprenorphine, and opioid receptor antagonists, e.g., naltrexone (Kampman etal. J Addict Med, 2015;9(5):358-367). However, such treatments are associated with limited success in preventing relapse and, in some cases, carry abuse liability themselves. The dopamine system is implicated in opioid reward (Fields & Margolis. Trends Neurosci. 2015;38(4):217-225; Steidl et al. Neurosci Biobehav Rev. 2017;83:72-82). D3 antagonists may be useful to treat opioid addiction and to potentiate the effects of prescribed opiates (Galaj et al. Neurosci Biobehav Rev, 2020;114:38-52). A compound’s effects on opioid-seeking behavior may be evaluated according to methods available to one of skill, including self-administration models, e.g., the IV self-administration reinstatement rodent model described by Fattoreetal. Methods Mol Biol. 2021;2201:231-245. In embodiments, a disclosed method for administering ketamine, such as esketamine, further comprises the administration of a conventional treatment for OUD, such as any of those above (e.g., opioid receptor agonists like methadone and buprenorphine, and opioid receptor antagonists like naltrexone), or others known to those of skill.

[229] In embodiments, treating OUD according to the disclosed methods comprises reducing opioid use or results in a reduction of opiate use. In embodiments, treating OUD comprises reducing opioid cravings or results in a reduction of opioid cravings. In embodiments, treating OUD comprises promoting abstinence from opiate use or results in abstinence from opiates. In embodiments, treating OUD comprises preventing relapse into opioid use. In embodiments, treating OUD comprises improving at least one symptom of OUD or reducing the severity of at least one diagnostic criterion of OUD.

[230] In embodiments, a reduction in opioid use refers to reducing the amount or frequency of opioid use, for example as assessed by urinalysis or saliva testing of opioid use biomarkers. Biomarkers of opioid use are described in, e.g., Stefanidou et al., Int J Clin Pract. 2010;64(12):1712-8; Kennedy & Dani, J Anal Toxicol. 2020;44(4):410-413; Valadbeigi & llbeigi, Rapid Commun Mass Spectrom. 2021 Mar 30;35(6):e9044.

[231] In embodiments, OUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, OUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. WO 2025 / 160483                                   PCT / US2025 / 013057 f. Sedative, Hypnotic, and Anxiolytic Use Disorder (SHAUD)

[232] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s intake of a sedative, a hypnotic, and / or an anxiolytic. In embodiments, the subject has sedative, hypnotic, or anxiolytic use disorder (SHAUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of SHAUD. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat SHAUD.

[233] In embodiments, the subject reduces or abstains from sedative, hypnotic, and / or anxiolytic use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[234] In embodiments, a method comprises administering a composition to a subject with SHAUD to treat the SHAUD. In embodiments, the method thereby treats the SHAUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat SHAUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat SHAUD. In embodiments, a subject is administered an esketamine OTF to treat SHAUD.

[235] “Sedatives, hypnotics, or anxiolytics use disorder” (SHAUD) refers to the disorder as defined, for example, in the DSM-5.

[236] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[237] In embodiments, treatment with a composition, either alone or with psychotherapy, treats SHAUD.

[238] In some embodiments, treating SHAUD comprises reducing any one or more of a subject’s sedative, hypnotic, or anxiolytic intake, a subject’s sedative, hypnotic, or anxiolytic cravings, and a subject’s cue reactivity to substance stimuli. A reduction in sedative, hypnotic, or anxiolytic use refers to reducing the amount or frequency of sedative, hypnotic, or anxiolytic use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using an assessment, e.g., the Severity of Dependence Scale (SDS). See, e.g., Tenore, Addict Dis. 2010 Oct;29(4):436-48. Reductions in cravings and / or cue reactivity may be determined according to methods available to one of skill in the art, e.g., use of an assessment, such as the Brief Substance Craving Scale (BCBS) or the Benzodiazepine Craving Questionnaire. See, e.g., Mol et al., Addiction. 2003 Aug;98(8):1143-52.

[239] Sedatives, hypnotics, and anxiolytics can cause CNS depression, which may be fatal. Exemplary CNS depressants include benzodiazepines, e.g., alprazolam, clonazepam, lorazepam, diazepam, chlordiazepoxide, and barbiturates, such as phenobarbital, pentobarbital, and butobarbital. Other classes of drugs have properties that share a similar mechanism of action with benzodiazepine and barbiturates, including alcohol. These agents mediate gamma-aminobutyric acid (GABA) effects, producing inhibitory effects within the central nervous system. In embodiments, a disclosed method is used to treat sedative, hypnotic, and anxiolytic use disorder.

[240] Criteria for sedative, hypnotic, and anxiolytic use disorder are available to one of skill. In one example, the DSM-5 describes sedative, hypnotic, and anxiolytic use disorder and criteria for the same, for example: Sedatives, hypnotics, or anxiolytics are often taken in larger amounts or over a longer period than was intended; There is a persistent desire or unsuccessful efforts to cut down or control sedative, hypnotic, or anxiolytic use; A great deal of time is spent in activities necessary to obtain the sedative, hypnotic, or anxiolytic; use the sedative, hypnotic, or anxiolytic; or recover from its effects.

[241] In embodiments, a disclosed method alleviates or reduces the signs or symptoms of sedative, hypnotic, and anxiolytic use disorder. In embodiments, treating sedative, hypnotic, and anxiolytic use disorder comprises reducing use of one or more of a sedative, hypnotic, and anxiolytic or results in a reduction of use of the same. In embodiments, treating sedative, hypnotic, and anxiolytic use disorder comprises reducing cravings for one or more of a sedative, hypnotic, and anxiolytic or results in a reduction of cravings for the same. In embodiments, treating sedative, hypnotic, and anxiolytic use disorder comprises promoting abstinence from one or more of a sedative, hypnotic, and anxiolytic or results in abstinence from the same. In embodiments, treating sedative, hypnotic, and anxiolytic use disorder comprises preventing relapse into use of one or more of a sedative, hypnotic, and anxiolytic. In embodiments, treating sedative, hypnotic, and anxiolytic use disorder comprises improving at least one symptom of sedative, hypnotic, and anxiolytic use disorder or reducing the severity of at least one diagnostic criterion of sedative, hypnotic, and anxiolytic use disorder.

[242] In embodiments, the SHAUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, SHAUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. g. Stimulant Use Disorder (StUD)

[243] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s stimulant intake. In embodiments, the subject has stimulant use disorder (StUD). In some embodiments, the subject has caffeine use disorder. In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of StUD. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat StUD.

[244] In embodiments, the subject reduces or abstains from stimulant use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[245] In embodiments, a method comprises administering a composition to a subject with StUD to treat the StUD. In embodiments, the method thereby treats the StUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat StUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat StUD. In embodiments, a subject is administered an esketamine OTF to treat StUD. WO 2025 / 160483                                   PCT / US2025 / 013057

[246] “Stimulant use disorder” (StUD) refers to the disorder as defined, for example, in the DSM-5.

[247] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[248] In embodiments, treatment with a composition, either alone or with psychotherapy, treats StUD.

[249] In some embodiments, treating StUD comprises reducing any one or more of a subject’s stimulant intake, a subject’s stimulant cravings, and a subject’s cue reactivity to substance stimuli. A reduction in stimulant use refers to reducing the amount or frequency of stimulant use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment, e.g., the Severity of Dependence Scale (SDS). Reductions in cravings and / or cue reactivity may be determined according to methods available to one of skill in the art, e.g., use of an assessment, such as the Brief Substance Craving Scale (BCBS) or the Stimulant Craving Questionnaire-Brief (STCQ).

[250] Stimulants increase synaptic levels of the monoamines dopamine, serotonin, and norepinephrine. Both the dopaminergic and the noradrenergic systems play critical roles in the effects of stimulants, including reward (Sofuoglu & Sewell, Addict Biol. 2009; 14(2): 119-129; Wise, Brain Res. 1978;152(2):215-47). Non-limiting examples of stimulants include amphetamines, methamphetamine, and cocaine. Nicotine / tobacco may also be considered a stimulant. In embodiments, a disclosed method is used to treat stimulant use disorder. In embodiments, a disclosed method is used to treat cocaine use disorder. In embodiments, a disclosed method is used to treat methamphetamine use disorder.

[251] Criteria for stimulant use disorder are available to one of skill. For example, exemplary DSM-5 criteria include: The stimulant is often taken in larger amounts or over a longer period than was intended; There is a persistent desire or unsuccessful efforts to cut down or control stimulant use; A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or recover from its effects. In embodiments, a disclosed method alleviates or reduces the signs or symptoms of stimulant use disorder.

[252] In embodiments, a disclosed method alleviates or reduces the signs or symptoms of stimulant use disorder. In embodiments, treating stimulant use disorder comprises reducing use of stimulants or results in a reduction of stimulant use. In embodiments, treating stimulant use disorder comprises reducing stimulant cravings or results in a reduction of stimulant cravings. In embodiments, treating stimulant use disorder comprises promoting abstinence from stimulants or results in abstinence from stimulants. In embodiments, treating stimulant use disorder comprises preventing relapse into stimulant use. In embodiments, treating stimulant use disorder comprises improving at least one symptom of stimulant use disorder or reducing the severity of at least one diagnostic criterion of stimulant use disorder. In embodiments, the stimulant is cocaine. In embodiments, the stimulant is an amphetamine, such as methamphetamine.

[253] In embodiments, a reduction of stimulant use or abstinence therefrom may be determined using biological samples. In one example, a subject’s hair or urine may be assessed to evaluate the presence of cocaine and benzoylecgonine, a metabolite thereof. See, e.g., Bravo et al., Toxins (Basel). 2022 Apr 13;14(4):278 and Pan et al., Fa YiXue Za Zhi. 2018;34(4):375-378. In embodiments, stimulant cravings may WO 2025 / 160483                                   PCT / US2025 / 013057 be assessed using methods available to one of skill, including self-administration models, e.g., the hold down procedures described by Zimmer & Roberts, Psychiatric Disorders, 2011 ;279—290.

[254] Current treatment options for stimulant use disorder include contingency management, CBT, acupuncture, antidepressants, dopamine agonists, antipsychotics, anticonvulsants, disulfiram, opioid agonists, N-Acetylcysteine, and psychostimulants (Ronsley et al., PLoS One. 2020; 15(6):e0234809). Psychostimulants, for example, bupropion and dexamphetamine, are treatment options. In contrast, dopamine modulators, including agonists and antagonists, appear to lack efficacy in StUDs, such as cocaine use disorder (Cochrane Database Syst Rev. 2015 May; 2015(5): CD003352; id., Syst Rev. 2016 Mar; 2016(3): CD006306).

[255] In embodiments, the StUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the StUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. h. Nicotine Dependence and Tobacco Use Disorder (NTUD)

[256] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s nicotine or tobacco intake. In embodiments, the subject has nicotine or tobacco use disorder (NTUD). In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of NTUD. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat NTUD.

[257] In embodiments, the subject reduces or abstains from nicotine and / or tobacco use prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[258] In embodiments, a method comprises administering a composition to a subject with NTUD to treat the NTUD. In embodiments, the method thereby treats the NTUD. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat NTUD. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat NTUD. In embodiments, a subject is administered an esketamine OTF to treat NTUD.

[259] “Nicotine or tobacco use disorder” (NTUD) refers to the disorder defined, for example, in the DSM-5.

[260] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[261] In embodiments, treatment with a composition, either alone or with psychotherapy, treats NTUD.

[262] In some embodiments, treating NTUD comprises reducing any one or more of a subject’s nicotine and / or tobacco intake, a subject’s nicotine and / or tobacco cravings, and a subject’s cue reactivity to substance stimuli. A reduction in nicotine and / or tobacco use refers to reducing the amount or frequency of nicotine and / or tobacco use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment, e.g., the Severity of Dependence WO 2025 / 160483                                   PCT / US2025 / 013057 Scale (SDS) or the Fagerstrom Test for Nicotine Dependence. See, e.g., Rustin, Am Fam Physician. 2000 Aug 1 ;62(3):579-84, 591-2. Reductions in cravings and / or cue reactivity may be determined according to methods available to one of skill in the art, e.g., use of an assessment, such as the Brief Substance Craving Scale (BCBS) or the Questionnaire of Smoking Urges (QSU).

[263] The determination of nicotine dependence or tobacco use disorder is known to one of skill, such as by reference to the DSM-5 or to Baker et al., Addiction, 2012;107(2):263-275. For example, the criteria provided by the DSM-5 include: Unsuccessful efforts to quit or reduce intake of tobacco; Inordinate amount of time acquiring or using tobacco products; Cravings for tobacco.

[264] In embodiments, a disclosed method alleviates or reduces the signs or symptoms of nicotine dependence or tobacco use disorder. In embodiments, treating nicotine dependence or tobacco use disorder comprises reducing use of nicotine or tobacco or results in a reduction of nicotine or tobacco use. In embodiments, treating nicotine dependence or tobacco use disorder comprises reducing nicotine or tobacco cravings or results in a reduction of nicotine or tobacco cravings. In embodiments, treating nicotine dependence or tobacco use disorder comprises promoting abstinence from nicotine or tobacco use or results in abstinence from nicotine or tobacco. In embodiments, treating nicotine dependence or tobacco use disorder comprises preventing relapse into nicotine or tobacco use. In embodiments, treating nicotine dependence or tobacco use disorder comprises improving at least one symptom of nicotine dependence or tobacco use disorder or reducing the severity of at least one diagnostic criterion of nicotine dependence or tobacco use disorder. In embodiments, nicotine cravings are assessed by evaluating nicotine seeking behavior. A compound’s effects on nicotine seeking behavior may be evaluated according to methods available to one of skill, including self-administration, place conditioning, and intracranial self-stimulation paradigms in rodents (O’Dell & Khroyan, Pharmacol Biochem Behav. 2009;91 (4):481-488).

[265] In embodiments, NTUD is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, NTUD is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. i. Other Substance Use Disorders

[266] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to reduce a subject’s substance intake, wherein the substance is one other than described above, or that does not have its own DSM-5 diagnosis. In embodiments, the subject has another substance use disorder. In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of another substance use disorder. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat another substance use disorder.

[267] In embodiments, the subject reduces or abstains from use of the other substance prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more WO 2025 / 160483                                   PCT / US2025 / 013057 than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[268] In embodiments, a method comprises administering a composition to a subject with another substance use disorder to treat the other substance use disorder. In embodiments, the method thereby treats the other substance use disorder. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat the other substance use disorder. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat the other substance use disorder. In embodiments, a subject is administered an esketamine OTF to treat the other substance use disorder.

[269] The determination of other substance use disorder will be appreciated by one of skill.

[270] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[271] In embodiments, treatment with a composition, either alone or with psychotherapy, treats the other substance use disorder.

[272] In some embodiments, treating the other substance use disorder comprises reducing any one or more of a subject’s other substance intake, a subject’s other substance cravings, and a subject’s cue reactivity to other substance-related stimuli. A reduction in other substance use refers to reducing the amount or frequency of other substance use, for example as assessed by biological specimen testing, e.g., blood analysis, breath analysis, hair analysis, nail analysis, or as assessed by using a self-reported assessment. Reductions in cravings and / or cue reactivity may be determined according to methods available to one of skill.

[273] In embodiments, the other substance use disorder is comorbid with another SUD, a behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the other substance use disorder is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition.

[274] For each of the above sections, embodiments, uses of disclosed compositions and methods, and details of the advantages and benefits of treatment, are all exemplary. Similar language, in sections on different SUDs (e.g., in the section on AUD or OUD) also may be applicable, depending on context. Consequently, it will be readily understood that alternative embodiments for each of the SUD sections above can be provided by taking the embodiments from one or more other SUD sections (or from the behavioral addictions section that follows), and changing the specific SUD as appropriate, depending on various distinctions known in view hereof.

[275] For example, with each of the SUDs herein, “reducing” substance use refers to reducing the amount or frequency of the substance use, such as assessed by standardized screening tools like those described herein, and within the knowledge of ordinary skill, and wherein “substance use” refers to the substance “of abuse” for the SUD being treated. In embodiments, “reducing” substance use refers to a reduction in daily engagement in substance use, a reduction in the time spent engaging in substance use per day, or a reduction in the frequency of engaging in the substance use, such as a reduction in the percentage of days engaging in the substance use WO 2025 / 160483                                   PCT / US2025 / 013057 in general, or a reduction in the percentage of heavy engagement of substance use days. In embodiments, “reducing” substance use refers to an increase in the time to any engagement in the substance use or time to the first heavy engagement of the substance use. Herein, “heavy engagement” and “heavy” in relation to a substance use will refer to the relative quantity of such substance use, as known in the art.

[276] Herein, “abstinence” or “in abstinence from” substance use refers to not engaging in the substance use. In embodiments, “promoting” abstinence or “promotion of’ abstinence from substance use refers to help maintaining abstinence from the substance use, in particular after at least 1 day of not engaging in the substance use, for example, maintaining abstinence from the substance use for a period of at least 1 day, at least 1 week, at least 1 month, or at least 1 year. Herein, a SUD patient “in abstinence from” a substance use refers to a subject in abstinence from the substance use for a period of at least 1 day, at least 1 week, at least 1 month, or at least 1 year. Herein, the term “at least 1 day, at least 1 week, at least 1 month, or at least 1 year” is shorthand for and as if stating expressly, “at least 1 day, including 1 day, 2 days, 3 days, 4 days, 5 days, and 6 days; for at least 1 week, including 1 week, 2 weeks, and 3 weeks; for at least 1 month, including 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months; for at least 6 months, at least 9 months, or at least 1 year, including for greater than 1 year.”

[277] If not otherwise specified, each time period herein will be measured from baseline.

[278] Herein, “relapse into” substance use refers to engaging in substance use following a period of abstinence from substance use, for example following a period of abstinence of at least 1 day, at least 1 week, at least 1 month, or at least 1 year. Herein, “preventing relapse into” substance use refers to the prevention of engaging in substance use by a subject after the subject has stopped the substance use, in particular after 1 day or more of not engaging in the substance use. In embodiments, “1 day or more of not engaging in the substance use” also encompasses a permanent stoppage of the substance use. In embodiments, the term encompasses a delay in the resumption of the substance use as compared to the time to resumption by a subject that is not administered a compound of the invention using the disclosed methods. The delay in resumption can be for at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[279] In embodiments, a subject with an SUD is administered a disclosed composition, such as an esketamine OTF. In embodiments, administration of the composition will be effective to treat the SUD.

[280] In embodiments, a subject with an SUD is administered a disclosed composition with adjunctive psychotherapy. In embodiments, administration of the composition together with psychotherapy will be effective to treat the SUD.

[281] In embodiments, a subject with an SUD undergoes a KAP treatment regimen. In embodiments, the KAP treatment regimen will be effective to treat the SUD.

[282] In embodiments, “effective to treat the SUD” will be shown by one or more of: (a) a reduction in the substance use, (b) a reduction in drive or urge to engage in the substance use, (c) a promotion of abstinence from the substance use, (d) a prevention of relapse into the substance use, (e) an improvement in at least one WO 2025 / 160483                                   PCT / US2025 / 013057 symptom of the substance use disorder, or (f) a reduction in the severity of the substance use disorder.

[283] In embodiments, “effective to treat the SUD” will be shown by a measurable reduction in substance use or in the drive or urge to engage in substance use, for example as compared to a baseline determination made before treatment. In embodiments, the reduction in substance use is at least 15%, including 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100%, when measured from baseline. Such a comparison may be made at a time after baseline of, e.g., at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[284] In embodiments, “effective to treat the SUD” will be shown by a durable promotion of abstinence from substance use or prevention of relapse into substance use, when measured from the start of treatment, such as the first administration. In embodiments, the promotion of abstinence from substance use results in abstinence for at least 1 day, at least 1 week, at least 1 month, or at least 1 year, from the start of treatment. In embodiments, the reduction in substance use, reduction in drive or urge to engage in substance use, promotion of abstinence from substance use, prevention of relapse into substance use, and reduction in at least one symptom of the SUD that lasts for at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[285] In embodiments, “effective to treat the SUD” will be shown by a measurable improvement in at least one symptom of the SUD. In embodiments, treating a subject according to a disclosed method will result in the subject having a reduction in at least one symptom of the SUD. In embodiments, treating a subject according to a disclosed method will result in the subject having an elimination of at least one symptom of the SUD. Such improvement, reduction, or elimination in a symptom may, for example, be compared to a baseline determination made before treatment.

[286] In embodiments, “effective to treat the SUD” will be shown by a reduction in the severity of the SUD. For example, a subject who has a SUD characterized as being “mild” when measured at baseline will no longer have a mild SUD; a subject who has a SUD characterized as being “moderate” when measured at baseline will no longer have a moderate SUD; and a subject who has a SUD characterized as being “severe” when measured at baseline will no longer have a severe SUD; with all such subjects having a SUD characterized as being of lower severity, or no longer having the SUD. A reduction in the severity of a SUD can be determined, e.g., based on an assessment for the SUD. Exemplary assessments are as disclosed or as known to one of skill.

[287] For example, an “assessment” may refer to any means or method used with a subject, whether before, during, after, or unrelated in time to a specific treatment protocol, to measure, estimate, or evaluate a nature, ability, symptom, disorder, or other characteristic of the subject, whether qualitatively or quantitatively, and whether performed by the therapist or other clinician (e.g., an interview), by the subject his or herself (e.g., a self-reported questionnaire), by a third-party human or by a medical or other device (e.g., a medical sensor or biosensor, a watch or fitness tracker), and whether graded by a human decision-maker or an artificial intelligence (Al), using machine learning (ML), or with a computer algorithm.

[288] Non-limiting examples of assessments, with exemplary use cases, include the following:

[289] The Severity of Alcohol Dependence Questionnaire (SADQ) (Stockwell et al. Br J Addict. WO 2025 / 160483                                   PCT / US2025 / 013057 1983;78(2): 145-155). A 20 item clinical screening tool designed to measure the presence and level of alcohol dependence, taking approximately 5 minutes. It is designed to assess people that are currently drinking and therefore generally (“generally,” here and elsewhere, means “in a preferred embodiment,” but does not mean “necessarily”) will only be administered once, at screening before subjects undergo alcohol detoxification.

[290] The Mini International Neuropsychiatric Interview 5 (MINI 5) (Sheehan et al. J Clin Psychiatry. 1998;59 Suppl 20:22-57). Screens for comorbid psychiatric disorders, taking approximately 20 minutes.

[291] The Columbia Suicide Severity Rating Scale (C-SSRS) (Mundt et al. J Clin Psychiatry. 2013;74(9):887-893). Screens for acute and recent suicide and self-harm thoughts and behaviors, taking approximately five minutes to complete. May be completed at screening, at baseline, before each ketamine session, after each ketamine session, and in some exemplary embodiments, at 3, 6, and 9-month follow-ups.

[292] The Alcohol Dependence Syndrome section of the SCID-5-CT (Clinical Trials Version) (First et al. World Psychiatry. 2015; 14(1 ):82-90). A semi-structured interview taking approximately ten minutes.

[293] The Patient Health Questionnaire (PHQ-9) (Kroenke et al. J Gen Intern Med. 2001 ;16(9):606-613). A brief self-administered screening questionnaire for depressive symptoms, which may be administered at screening, baseline, the final therapy session, and at follow-up, taking approximately 5 minutes.

[294] Generalized Anxiety Disorder 7 (GAD-7) (Spitzer et al. Arch Intern Med. 2006; 166(10):1092-1097). A self-reported questionnaire for screening and severity measuring of GAD. Generally administered at screening, baseline, the final therapy session, and at follow-up, taking approximately 5 minutes.

[295] Short Inventory of Problems for Alcohol (SIP) (Kiluk et al. Psychol Addict Behav. 2013;27(1 ):307-14) SIP for alcohol is a 15-item instrument that assesses the self-attributed consequences of drinking, taking approximately 5 minutes. This generally will be completed at screening, baseline, the final therapy session, and at 3, 6, and 9 months’ follow-up.

[296] The Alcohol Timeline Follow Back (TLFB) (Sobell et al. Subst Use Misuse. 2001 ;36(3):313-331) is a method of assessing daily drinking and recreational drug use over time. Patients generally will be given the TLFB diary after screening, data will be collected at each therapy session. After completion of therapy, a researcher generally will call on a monthly basis to collect data throughout the study. Further discussion of the diary generally will take place formally at 3, 6, and 9 months follow up.

[297] The Clinical Institute Withdrawal Assessment for Alcohol—Revised Version (CIWA-Ar) (Saltz et al. JAMA. 1994;272(7):519-523). This is a ten-item scale used in the assessment and management of alcohol withdrawal. Each item on the scale correlates to the severity of alcohol withdrawal. This may be administered at baseline and before each ketamine-assisted session, taking approximately 3 minutes.

[298] The Penn Alcohol Craving Scale (PACS) (Flannery et al. Alcohol Clin Exp Res. 1999;23(8): 12891295) is used to assess frequency, intensity and duration of thoughts about drinking, completed at the screening and baseline assessment, and at 3, 6, and 9 months’ follow-up.

[299] Obsessive Compulsive Drinking Scale (OCDS) (Anton et al. Alcohol Clin Exp Res. 1995;19(1):92- WO 2025 / 160483                                   PCT / US2025 / 013057 99) is used to measure obsessive and compulsive thoughts in relation to alcohol, completed at the screening and baseline assessment, and at 3, 6, and 9 months’ follow-up.

[300] Pittsburgh Sleep Quality Index (PSQI) (Buysse et al. Psych Res. 1989;28(2): 193-213), to assess the level of sleep disturbance, may be completed at screening, baseline, and 3, 6, and 9 months’ follow-up.

[301] Interpersonal reactivity Index (IRI) (Davis. JSAS Catalog of Selected Documents in Psychology. 1980;10:1-19) comprises 28 items answered on a 5 point scale, and measures different aspects of empathy and provides different subscales relating thereto. It may be administered at baseline, the final therapy session, and 3, 6, and 9 months’ follow-up to explore if these core aspects of empathy are modified by KAP.

[302] The Short Form (36) Health Survey (SF-36) is a gold standard subject-reported measure of quality of life that can be completed at baseline, and at 3, 6, and 9 months’ follow-up.

[303] The Self-Compassion Scale (SCS) (Neff. Self and Identity. 2003;2(2):85-101) Comprises 26 items answered on a 5 point scale, which measures core aspects of self-compassion, including components of mindfulness. It may be administered at baseline, the final therapy session, and 3, 6, and 9 months’ follow-up.

[304] The Trauma History Questionnaire (THQ) (Green. Trauma History Questionnaire. In B. H. Stamm (Ed.), Measurement of stress, trauma, and adaptation. Sidran Press; 1996:366-369) is a self-report measure that examines experiences with potentially traumatic events using a yes / no format. For each event endorsed, respondents are asked to provide the frequency of the event as well as their age at the time of the event. It may be administered once, at baseline.

[305] An assessment may be computer-assisted, and other assessments may be performed besides the assessments above. The term “computer-assisted” in “computer-assisted assessment” means an assessment comprising the use of electronic tools such as online tools, smartphones, wireless devices, or health apps (in some such examples, also known as “digital phenotyping”). Computer-assisted assessments may include use of an electronic psychiatric notes system, and may include the use of computer systems where the therapist and subject interact virtually (either synchronously or asynchronously), as well as where a subject only interacts with a computer (“computer” broadly meaning any electronic tool suitable for such purposes, including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; watches, fitness trackers, and personal electronic devices; and the like). The adjunctive psychotherapy provided according to disclosed methods may be “computer-assisted,” both in whole and in part.

[306] As also noted above, any “SUD” in this section may be replaced with a specific SUD such as disclosed herein, with such further modifications as will be appreciated by one of skill in view of the teachings herein. j. Behavioral Addictions

[307] In some aspects are provided methods of administering a disclosed composition, such as an esketamine OTF, to treat a behavioral addiction. In embodiments, the disclosed composition, such as the esketamine OTF, is used in the treatment of a behavioral addiction. In embodiments, the disclosed composition, such as the esketamine OTF, is administered to a subject in need thereof to treat a behavioral addiction. WO 2025 / 160483                                   PCT / US2025 / 013057

[308] In embodiments, the subject reduces or abstains from the compulsive behavior prior to treatment such as by more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 10 days, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, or more than 3 months.

[309] In embodiments, a method comprises administering a composition to a subject with an SUD to treat a behavioral addiction. In embodiments, the method thereby treats the behavioral addiction. In embodiments, a subject is administered a composition, such as comprising esketamine, to treat a behavioral addiction. In embodiments, a subject is administered an oral transmucosal dosage form of esketamine to treat a behavioral addiction. In embodiments, a subject is administered an esketamine OTF to treat a behavioral addiction.

[310] The determination of a behavioral addiction will be appreciated by one of skill. For example, behavioral addictions include gambling disorder, compulsive sexual behavior disorder, compulsive buying-shopping disorder, internet addiction, gaming disorder and internet gaming disorder, risk-taking addictions, kleptomania, pyromania, pornography addiction, technology addiction, binge eating disorder, “workaholism,” perfectionism, pathological skin picking, exercise addiction (including overtraining syndrome), excessive tanning, tattoo addiction, masturbation addiction, sex addiction, and love addiction, as well as such other behavioral addictions as will be known in the art. Different behavioral addictions are often referred to by multiple names, depending on the diagnostic system used (e.g., DSM-5, ICD-11), the edition of that system, and informal use; however, it will be readily appreciated that the specific terminology used herein will not be limiting, and a behavioral addiction may be known, e.g., by its underlying features, signs, and symptoms. Whether behavior rises to the level of “addiction” generally will depend on whether the behavior is compulsive and is out-of-control despite adverse consequences, and whether any such behavior may constitute a “behavioral addiction” will be ascertainable by those of skill.

[311] A behavioral addiction may be characterized as being mild, moderate, and severe. The severity of the behavioral addiction may be determined according to the classification scale of the DSM-5, if applicable, a patient-completed self-assessment, a questionnaire, a measure, an index score, another type of assessment, or otherwise using ordinary skill.

[312] In embodiments, the methods further comprise providing adjunctive psychotherapy to the subject.

[313] In embodiments, treatment with a composition, alone or with psychotherapy, treats a behavioral addiction.

[314] Herein, “reducing” a behavior or “reduction in” a behavior refers to reducing the amount or frequency of the behavior, such as assessed by standardized screening tools like those described herein, and within the knowledge of ordinary skill, and wherein “behavior” refers to the compulsive or problematic behavior characteristic of the behavioral addiction. In embodiments, “reducing” a behavior or “reduction in” a behavior refers to a reduction in daily engagement in the behavior, a reduction in the time spent engaging in the behavior per day, or a reduction in the frequency of engaging in the behavior, such as a reduction in the percentage of days engaging in the behavior in general, or a reduction in the percentage of heavy engagement of the behavior WO 2025 / 160483                                   PCT / US2025 / 013057 days. In embodiments, “reducing” a behavior or “reduction in” a behavior refers to an increase in the time to any engagement in the behavior or time to the first heavy engagement of the behavior day. Herein, “heavy engagement” and “heavy” in relation to a compulsive or problematic behavior will refer to the relative quantity of participation in or performance of the behavior, as known in the art.

[315] Herein, behavioral “abstinence” or “in abstinence from” a behavior refers to not engaging in the behavior. In embodiments, “promoting” behavioral abstinence or “promotion of” behavioral abstinence refers to help maintaining abstinence from the behavior, in particular after at least 1 day of not engaging in the behavior, for example, maintaining abstinence from the behavior for a period of at least 1 day, at least 1 week, at least 1 month, or at least 1 year. Herein, a behavioral addiction subject “in abstinence from” a behavior refers to a subject with a behavioral addiction in abstinence from the behavior for a period of at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[316] Herein, “relapse into” a behavior refers to engaging in a behavior following a period of abstinence from the behavior, for example following a period of behavioral abstinence of at least 1 day, at least 1 week, at least 1 month, or at least 1 year. Herein, “preventing relapse into” a behavior refers to the prevention of engaging in a behavior by a behavioral addiction subject after the subject has stopped the behavior, in particular after 1 day or more of not engaging in the behavior. In embodiments, “1 day or more of not engaging in the behavior” also encompasses a permanent stoppage of the behavior. In embodiments, the term encompasses a delay in the resumption of the behavior as compared to the time to resumption by a subject that is not administered a compound of the invention using the disclosed methods. The delay in resumption can be for at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[317] In embodiments, a subject with a behavioral addiction is administered a disclosed composition, such as an esketamine OTF. In embodiments, administration of the composition will be effective to treat the behavioral addiction.

[318] In embodiments, a subject with a behavioral addiction is administered a disclosed composition with adjunctive psychotherapy. In embodiments, administration of the composition together with psychotherapy will be effective to treat the behavioral addiction.

[319] In embodiments, a subject with a behavioral addiction undergoes a KAP treatment regimen. In embodiments, the KAP treatment regimen will be effective to treat the behavioral addiction.

[320] In embodiments, “effective to treat the behavioral addiction” will be shown by one or more of: (a) a reduction in the behavior, (b) a reduction in drive or urge to engage in the behavior, (c) a promotion of abstinence from the behavior, (d) a prevention of relapse into the behavior, (e) an improvement in at least one symptom of the behavioral addiction, or (f) a reduction in the severity of the behavioral addiction.

[321] In embodiments, “effective to treat the behavioral addiction” will be shown by a measurable reduction in a compulsive behavior or in the drive or urge to engage in a compulsive behavior, for example as compared to a baseline determination made before treatment. In embodiments, the reduction in a compulsive behavior is WO 2025 / 160483                                   PCT / US2025 / 013057 at least 15%, including 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100%, when measured from baseline. Such a comparison may be made at a time after baseline of, e.g., at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[322] In embodiments, “effective to treat the behavioral addiction” will be shown by a durable promotion of abstinence from a compulsive behavior or prevention of relapse into a compulsive behavior, when measured from the start of treatment, such as the first administration. In embodiments, the promotion of abstinence from a compulsive behavior results in abstinence for at least 1 day, at least 1 week, at least 1 month, or at least 1 year, from the start of treatment. In embodiments, the reduction in a compulsive behavior, reduction in drive or urge to engage in the compulsive behavior, promotion of abstinence from the compulsive behavior, prevention of relapse into the compulsive behavior, and reduction in at least one symptom of the compulsive behavior that lasts for at least 1 day, at least 1 week, at least 1 month, or at least 1 year.

[323] In embodiments, “effective to treat the behavioral addiction” will be shown by a measurable improvement in at least one symptom of the behavioral disorder. In embodiments, treating a subject according to a disclosed method will result in the subject having a reduction in at least one symptom of the behavioral disorder. In embodiments, treating a subject according to a disclosed method will result in the subject having an elimination of at least one symptom of the behavioral disorder. Such improvement, reduction, or elimination in a symptom may, for example, be compared to a baseline determination made before treatment.

[324] In embodiments, “effective to treat the behavioral addiction” will be shown by a reduction in the severity of the behavioral addiction. For example, a subject who has a behavioral addiction characterized as being “mild” when measured at baseline will no longer have a mild behavioral addiction; a subject who has a behavioral addiction characterized as being “moderate” when measured at baseline will no longer have a moderate behavioral addiction; and a subject who has a behavioral addiction characterized as being “severe” when measured at baseline will no longer have a severe behavioral addiction; with all such subjects having a behavioral addiction characterized as being of lower severity, or no longer having the behavioral addiction. A reduction in the severity of a behavioral addiction can be determined, e.g., based on an assessment for the behavioral addiction. Exemplary assessments are disclosed herein or will be known to one of skill in the art.

[325] In embodiments, the behavioral addiction is comorbid with a SUD, another behavioral addiction, a mental health disorder, or a neurodegenerative disorder. In embodiments, the behavioral addiction is not comorbid with another condition. In embodiments, a disclosed method also treats the comorbid condition. In embodiments, a disclosed method further comprises administration of an additional active agent to treat the comorbid condition. F. Treatment with Adjunctive Psychotherapy

[326] In embodiments, a composition is administered with adjunctive psychotherapy.

[327] “Psychotherapy” includes Cognitive and Behavioral Therapies, Psychodynamic and Analytical Therapies, Humanistic and Integrative Therapies, Brief and Short-Term Therapies, Somatic and Body-Based Therapies, Family and Systems Therapies, Holistic and Transpersonal Therapies, Interpersonal and Supportive Therapies, and Specialized and Emerging Therapies. In embodiments, a composition is administered together with one or more Cognitive and Behavioral Therapies (e.g., Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), Behavioral Therapy, Cognitive Analytical Therapy, Contingency Management-Based Therapy, Community Reinforcement Approach-Based Therapy, Motivational Interviewing-Based Therapy, Motivational Enhancement-Based Therapy, Solution-Focused Brief Therapy, and Mindfulness-Based Cognitive Therapy), Psychodynamic and Analytical Therapies (e.g., Psychodynamic Psychotherapy, Psychoanalysis, Jungian Analysis, Object Relations Therapy, and AttachmentBased Psychotherapy), Humanistic and Integrative Therapies (e.g., Humanistic Integrative Psychotherapy, Person-Centered Psychotherapy, Gestalt Therapy, Existential Psychotherapy, Compassion-Focused Therapy, and Emotion-Focused Therapy), Brief and Short-Term Therapies (e.g., Brief Therapy and Solution-Focused Brief Therapy), Somatic and Body-Based Therapies (e.g., Body Psychotherapy and Somatic Psychotherapy), Family and Systems Therapies (e.g., Family Systems Therapy, Internal Family Systems Therapy, and Dyadic Psychotherapy), Holistic and Transpersonal Therapies (e.g., Transpersonal Psychotherapy, Meditation-Based Therapy, and Hypno-Psychotherapy), Interpersonal and Supportive Therapies (e.g., Interpersonal Therapy, Supportive Psychotherapy, and Attachment-Based Psychotherapy), and Specialized and Emerging Therapies (e.g., Neuro-Linguistic Psychotherapy and Transactional Analysis).

[328] “Psychotherapy” also includes psychosocial or behavioral therapy, including 12-step facilitation therapy (e.g., NIAAA, Project MATCH Monograph Series. Vol. 1, NIH Pub. No. 94-3722,1995 reprinted 1999); cognitive behavioral therapy (e.g., as in Crits-Cristoph et al. Arch Gen Psych 1999;56:493-502); interpersonal therapy (e.g., as in Barry et al. Psychol Addict Behav 2009;23(1):168-174); contingency management based therapy (e.g., as in Barry et al. Psychol Addict Behav2009;23(1):168-174; in Petry et al. J Consul Clin Psychol. 2005;73(2):354-59; or in Adams et al. Case Reports in Psychiatry. 2012;731638); community reinforcement approach based therapy (e.g., as in Roozen et al. Drug Alcohol Depend 2004;74:1-13); motivational interviewing based therapy (e.g., as in Stotts et al. J Consul Clin Psychol. 2001 ;69(5):858-62); motivational enhancement based therapy (e.g., as in McKee et al. Drug Alcohol Depend 2007;91:97-101); and meditation based therapy, such as transcendental meditation based therapy (e.g., as in Rohsenow et al. Addiction 2004;99(7):862-874 or Rohsenow et al. J Consul Clin Psychol. 2000;68(3):515-52).

[329] In embodiments, the psychosocial or behavioral therapy is any of 12-step facilitation (TSF), Motivational Enhancement Therapy (MET), and Cognitive-Behavioral Coping Skills Therapy (CBT).

[330] In embodiments, the psychosocial or behavioral therapy is any one of the 46 interventions disclosed in Miller & Wilbourne. Addiction. 2002; 97(3): 265-277, incorporated by reference as if fully set forth herein.

[331] “Psychotherapy” also includes “mindfulness-based relapse prevention” or “MBRP,” which refers to a mindfulness-based aftercare approach and integrates core aspects of relapse prevention with practices adapted from mindfulness-based stress reduction and mindfulness-based cognitive therapy. Identification of high-risk situations is central to the MBRP treatment. Participants may be trained to recognize early warning signs for relapse, increase awareness of internal (i.e., emotional and cognitive) and external (i.e., situational) cues previously associated with substance use, develop effective coping skills, and enhance self-efficacy. Mindfulness practices are intended to raise awareness of triggers, monitor internal reactions, and foster more skillful behavioral choices. The practices focus on increasing acceptance and tolerance of positive and negative physical, emotional, and cognitive states, such as craving, thereby decreasing the need to alleviate the discomfort by engaging in substance use (Bowen et al. Subst Abus. 2009;30(4):295-305).

[332] “Psychotherapy” also includes “psychedelic-assisted psychotherapy” (PAP) and “psychedelic-assisted therapy” (PAT), which both broadly refer to a range of approaches that involve at least one session where a subject is administered a “psychedelic” and is supported by or more trained professionals while under the effects of the drug (see, e.g., Schenberg. Front Pharmacol. 2018;9:733). Protocols have been developed for the standardization of procedures (see, e.g., Johnson et al. J Psychopharmacol. 2008;22(6):603-620; Grof. LSD Psychotherapy. 4th ed. MAPS; 2008; Passie. Healing with Enactogens. 1 st ed. MAPS; 2012; Sessa & Fischer. Drug Science, Policy and Law. 2015;2:2050324515578080.; Schmid etal. JPsychopharmacol. 2021 ;35(4):362-374; Greer & Tolbert. J Psychoactive Drugs. 1998;30(4):371-379; Mithoefer et al. Psychopharmacology (Berl). 2019;236(9):2735-2745; Mithoefer et al. J Psychopharmacol. 2013;27(1):28-39; and U.S. Pat. App. No. 2020 / 0360311). It will be appreciated that although the term “psychedelic-assisted psychotherapy” may be used, the administered compound need not be a “psychedelic” as the class is sometimes understood (e.g., as “classic” psychedelics), and also includes compounds having “dissociative” effects, such as ketamine and esketamine. “Dissociative,” in the context of the disclosure refers to a particular compound or class of compounds, such as ketamine or esketamine, having a dissociative effect when taken at high enough “dissociative” doses. A “dissociative effect,” in the context hereof, refers to a subjective alteration in perception, cognition, emotion, or consciousness, as will be attributed to and associated with the administration of ketamine at certain doses (i.e., dissociative doses), as will be appreciated by those in the art. Although a determination of dissociative effects may be made by a subject following administration of a disclosed composition, such determination also may be made by reference to psychometric rating scales as known in the art, for example, the Hallucinogen Rating Scale (HRS), the Mystical Experience Questionnaire (MEQ), or the Addiction Research Center Inventory (ARCI) (Bouso et al. Hum Psychopharmacol. 2016;31 (5):356-372), i.e., those used also with “psychedelic” compounds, or additionally with those specific to dissociatives. Thus, for clarity, terms such as “ketamine-assisted psychotherapy” (KAP) and “ketamine-assisted therapy” (KAT) may be preferred.

[333] In embodiments, a method comprises ongoing support, including adjunctive psychotherapy. Disclosed methods accordingly may comprise drug-assisted sessions, which may comprise psychotherapy, as well as further (non-drug-administration) sessions, which also may comprise psychotherapy, e.g., one or more psychotherapeutic modalities. Thus, a subject may receive psychotherapy on days or in sessions where the subject does not receive a disclosed composition, such as an esketamine OTF. In embodiments, a method WO 2025 / 160483                                   PCT / US2025 / 013057 comprises one or more adjunctive medications (e.g., an additional active agent).

[334] The term “therapist” may be used to refer to a person who treats a subject according to disclosed methods, however it will be understood that the person, depending on the type of psychotherapy and the specific embodiment, may be a psychiatrist, clinical psychologist, clinical therapist, psychotherapist, or other trained counselor, facilitator, or guide, and who may or may not be a trained addiction specialist or counselor, substance abuse specialist or counselor, or alcohol abuse specialist or counselor. The “therapist” generally will be trained or certified in the particular psychotherapy modality used, and for example may be certified in the use of the treatment manual where a form of manualized KAP is used, and may have completed the appropriate training in delivering that form of KAP, and likewise for other psychotherapy modalities.

[335] In embodiments, an exemplary treatment protocol comprises: (1) an optional detoxification phase (e.g., a period of time that the subject abstains from substance use), (2) an initial eligibility check, (3) a medical examination, (4) a psychological assessment, (5) a treatment phase, and (6) ongoing support (e.g., adjunctive medication and / or additional psychotherapy).

[336] For purpose of illustration, one exemplary treatment protocol comprises: (1) screening and initial eligibility check; (2) individualized baseline phase, e.g., 4 one-hour long phone calls between subject and clinician and daily self-reported measures; (3) treatment phase, e.g., esketamine dosing session followed by a psychotherapy session on the subsequent day for 3 consecutive weeks, and a fourth week of psychotherapy alone; and (4) follow-up interview, e.g., 2 weeks after treatment completion.

[337] In an additional exemplary embodiment, the treatment protocol comprises a pre-assessment eligibility check, an individualized baseline phase, 3 esketamine sessions, non-drug psychotherapy sessions, and a follow-up interview after treatment completion. In embodiments, subjects will receive 7 sessions of psychotherapy, spread over a 4-week course, which includes 3 esketamine administrations and a final posttreatment interview, 2 weeks after the end of the therapeutic course.

[338] In embodiments, the pre-assessment eligibility check is used to select subjects for treatment by a disclosed method. For example, in some embodiments, the pre-assessment eligibility check is used to identify subjects who are hazardous drinkers. In embodiments, a disclosed method is used to treat high risk drinkers. In embodiments, a disclosed method is used to treat subjects having moderate AUD. In embodiments, the preassessment eligibility check is used to identify subjects having moderate or severe OUD. In embodiments, a disclosed method is used to treat subjects having moderate or severe OUD.

[339] In embodiments, the pre-assessment eligibility check comprises using the Alcohol Use Disorders Identification Test (AUDIT) (Reinert & Allen. Alcohol Clin Exp Res. 2002;26(2):272-279). Hazardous drinking is typically indicated by an AUDIT score range of 8-15. In embodiments, a subject having an AUDIT score of between about 8 and 15 is selected for treatment. High risk drinking is typically indicated by an AUDIT score of 16-19. In embodiments, a subject having an AUDIT score of between about 8 and 15 is selected for treatment. In embodiments, a subject is selected for treatment if the subject is a hazardous drinker. In embodiments, a WO 2025 / 160483                                   PCT / US2025 / 013057 subject is selected for treatment if the subject is a high risk drinker. In embodiments, a subject is selected for treatment based on an AUDIT score over 8, 9,10,11,12,13,14,15,16,17, or 18.

[340] In embodiments, the pre-assessment eligibility check comprises using the SCID-5 Alcohol Use Disorder Screener. According to the SCID-5 Alcohol Use Disorder Screener, the presence of 4-5 symptoms indicates moderate AUD. In embodiments, a subject having a score of 4 or 5 using the SCID-5 AUD Screener is considered to have moderate AUD, and will be selected for treatment by a disclosed method.

[341] In embodiments, the pre-assessment eligibility check comprises using the Patient Medication Questionnaire (PMQ). The PMQ is a 26-question assessment tool using 0-4 point scale to assess subjects taking opioids. A score of 25-30 indicates problematic / moderate opioid use. In embodiments, a subject having a score of 25-30 indicates moderate OUD, and is selected for treatment according to a disclosed method.

[342] In embodiments, the pre-assessment eligibility check comprises evaluating the subject for the presence of a comorbid condition. In embodiments, a subject having a comorbid condition may be excluded from a disclosed method. Hence, in some embodiments, a disclosed method is used to treat a subject with an SUD that does not have a comorbid condition. Comorbid conditions include, for example, certain mental health disorders (e.g., depression). Thus, in some embodiments, a disclosed method is used to treat a subject with an SUD that does not have depression. In embodiments, a disclosed method is used to treat a subject with AUD that does not have depression. In embodiments, a disclosed method is used to treat a subject with OUD that does not have depression. In embodiments, a disclosed method is used to treat a subject with an SUD that does not have a pain condition. In embodiments, a disclosed method is used to treat a subject with AUD that does not have a pain condition. In embodiments, a disclosed method is used to treat a subject with OUD that does not have a pain condition. Evaluating a subject for the presence of a comorbid condition can be standard techniques in the art, including evaluation by a medical professional, subject assessments, laboratory diagnostics, and other routine procedures that will be known to one of skill.

[343] In embodiments, the method comprises a pre-treatment assessment of the subject’s SUD, which may be referred to herein as a “baseline phase.” In embodiments, the baseline phase is used to establish a baseline (pre-treatment) assessment of the extent of the subject’s SUD symptoms. Suitable assessment techniques and tools are described herein or are otherwise known to one of skill. In embodiments, the baseline phase is individualized, based on the particular needs of a specific subject. In embodiments, the baseline phase comprises evaluating a subject by phone (e.g., using a phone call between a subject and a treating clinician). In embodiments, the baseline phase comprises multiple phone assessments. In one exemplary protocol, the baseline procedure comprises 4 one-hour long phone calls. In embodiments, the baseline phase comprises evaluating the subject using daily self-reported measures provided by the subject.

[344] In embodiments, the duration of the baseline phase is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, less than 2 weeks (e.g., 8 days, 9 days, 10 days, 11 days, 12 days, 13 days), 2 weeks, less than 3 weeks (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days), 3 weeks, less than 4 weeks (e.g., 22 days, WO 2025 / 160483                                   PCT / US2025 / 013057 23 days, 24 days, 25 days, 26 days, 27 days), 4 weeks, or greater than 4 weeks. In embodiments, there is no baseline phase.

[345] In embodiments, a disclosed method comprises a treatment phase. The treatment phase comprises administering esketamine (e.g., formulated as an oral thin film) to the subject. In embodiments, the treatment phase comprises a single esketamine administration session. In embodiments, the treatment phase comprises multiple esketamine administration sessions. In embodiments, the treatment phase comprises 3 esketamine administration sessions. In embodiments, the treatment phase comprises 6 esketamine administration sessions. In embodiments, there is no at-home dosing or self-administration.

[346] For purposes of illustration, in one exemplary protocol, the treatment phase comprises 3 esketamine administration sessions that take place over the course of 3 weeks. In embodiments, the first week comprises one esketamine administration session followed by a non-drug psychotherapy session on the subsequent day. In embodiments, the second week comprises the second esketamine administration session followed by a nondrug psychotherapy session on the subsequent day. In embodiments, the third week comprises the third esketamine administration session followed by a non-drug psychotherapy session on the subsequent day. In embodiments, the treatment phase comprises a fourth week. In embodiments, the fourth week comprises a psychotherapy session alone (i.e., no esketamine administration session).

[347] In embodiments, the treatment phase comprises 6 esketamine administration sessions that take place over the course of 3 weeks. In embodiments, the first week comprises two separate esketamine administration sessions, each followed by a non-drug psychotherapy session (e.g., esketamine sessions 1 and 2). In embodiments, the second week comprises two separate esketamine administration sessions, each followed by a non-drug psychotherapy session (e.g., esketamine sessions 3 and 4). In embodiments, the third week comprises two separate esketamine administration sessions, each followed by a non-drug psychotherapy session (e.g., esketamine sessions 5 and 6). In embodiments, the two esketamine administration sessions (e.g., the esketamine administration sessions in the same week) are 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days apart. In embodiments, the non-drug psychotherapy session is on the same day as the esketamine administration session. In embodiments, the non-drug psychotherapy session is on the subsequent day following the esketamine administration session.

[348] In embodiments, a disclosed method comprises providing the subject with psychotherapy. In embodiments, the effects of a disclosed method will be dependent on the psychotherapy, such as the ketamine-assisted psychotherapy (KAP), that accompanies the administration of ketamine. For example, without psychotherapy, and without the advantages provided herein, the effects of the closest comparable methods tend to wane in 10-14 days. Psychotherapy, in embodiments, enables a subject to integrate the subjective drug experience and create durable change (e.g., long-term drug or alcohol abstinence). Psychotherapy includes both individual modalities and group therapy (e.g., group-talk therapy, 12-step programs, group counseling). In embodiments, group therapy comprises cohorts of 4-10 individuals.

[349] In embodiments, the ketamine-assisted psychotherapy (KAP) is provided based on the protocols of Ketamine for reduction of Alcohol REIapse, or “KARE.” One therapy program in accordance with KARE is a protocol of seven therapy sessions and three ketamine infusions to help the subject develop an enjoyable and meaningful life without alcohol. This protocol is disclosed in the KARE Therapy Programme Guidebook (University of Exeter, 2021), the entirety of which is incorporated by reference as if fully set forth herein. In some relevant aspects, KARE relates to the theme of relapse prevention (i.e., skills and strategies to reduce the likelihood of relapse and maintain abstinence), also known as ‘Risk Reduction Strategies.’ The focus is on identifying and coping with high-risk situations, coping with cravings, recognizing and tackling early warning signs for lapse, restructuring unhelpful thinking, and emergency lapse management. In some other relevant aspects, KARE relates to the theme of ‘Promoting Well Being,’ which deals with issues such as purpose, meaning and life enjoyment, and skills for coping with life’s problems and stresses. Each therapy session introduces a relaxation technique, so the subject will be familiar with seven relaxation techniques by the end of the course. The subject is also asked to complete a journal and assignments between the sessions relating to that session’s topics.

[350] Although in some embodiments, the KAP provided is inspired by or based on KARE, it will be appreciated that the methods of KARE may not be, and in embodiments will not be, the same as the methods of this disclosure. As an example, published KARE protocols involve ketamine infusions, unlike embodiments comprising oral transmucosal administration of esketamine. In embodiments, the use of oral transmucosal esketamine provides advantages over ketamine infusions. Advantages include a more rapid onset and offset of action. As another example, a KARE-based clinical trial (NCT02649231) explored one protocol for the combined use of psychological therapy and ketamine as a possible treatment for alcoholism, unlike embodiments using different protocols and, among other things, comprising different doses of ketamine. In some disclosed embodiments, the ketamine dose is different from the equivalent of 0.8 mg / kg IV over 45 minutes as administered therein. In embodiments, the number of ketamine administration sessions (i.e., sessions in which ketamine is administered) is not three sessions. In embodiments, the number of drug administration sessions (i.e., sessions in which esketamine, such as an esketamine OTF, is administered) is six sessions. In embodiments, the number of drug administration sessions is other than six sessions, such as five sessions, seven sessions, four sessions, eight sessions, three sessions, nine sessions, two sessions, ten sessions, one session, or greater than ten sessions.

[351] In embodiments, a disclosed method comprises providing the subject with group psychotherapy. In embodiments, group therapy comprises cohorts of 4-10 individuals. In embodiments, group therapy comprises cohorts of individuals unified by circumstances or type of experiences (e.g., law enforcement officers, firefighters, veterans, alcoholics). Alcoholics Anonymous (AA) and other 12-step group programs have been studied extensively in treatment and community settings and are associated with better recovery outcomes (Kaskutas LA, Subbaraman MS, Witbrodt J, Zemore SE. Effectiveness of Making Alcoholics Anonymous Easier: a group format 12-step facilitation approach. J Subst Abuse Treat. Oct 2009;37(3):228-39. doi:10.1016 / j.jsat.2009.01.004; Tonigan JS, Toscova R, Miller WR. Meta-analysis of the literature on Alcoholics Anonymous: sample and study characteristics moderate findings. J Stud Alcohol. Jan 1996;57(1 ):65-72. doi:10.15288 / jsa.1996.57.65). Additionally, observational studies have demonstrated about twice the rate of abstinence among 12-step group program attendees versus those who are recovering from addiction and not attending group meetings (TimkoC. Outcomes of AA for special populations. Recent Dev Alcohol 2008; 18:37392. doi:10.1007 / 978-0-387-77725-2_21). Positive results from randomized trials of 12-step facilitation also strongly suggest a causal relationship between 12-step involvement and substance use recovery. 12-step programs have been the standard of care for AUD and SUD for generations, with scholars theorizing that the social structures of these groups are an integral part of their effectiveness (Moos RH. How and why twelve-step self-help groups are effective. Recent Dev. Alcohol. 2008;18:393-412. doi: 10.1007 / 978-0-387-77725-2_22).

[352] In embodiments, a disclosed method comprises providing the subject with psychotherapy comprising mindfulness-based interventions. Non-limiting examples of mindfulness-based interventions include mindfulness-based relapse prevention (MBRP), mindfulness-based stress reduction (MBSR), mindfulnessbased cognitive therapy (MBCT), dialectical behavior therapy, acceptance and commitment therapy, mindfulness interviewing, and cognitive-behavioral therapy (CBT).

[353] MBRP (Hendershot et al. Subst Abuse Treat Prev Policy. 2011 ;6:17) incorporates core elements of mindfulness skills into relapse prevention. Mindfulness can be defined as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally” (Kabat-Zinn. Catalyzing movement towards a more contemplative / sacred-appreciating / non-dualistic society." Meeting of the working group. 1994) and has been embedded across a range of therapeutic interventions, including CBT for depression (Teasdale et al. J Consult Clin Psychol. 2000;68(4):615-623) and stress-reduction (Kabat-Zinn et al. Am J Psychiatry. 1992; 149(7):936-943). In relation to relapse prevention, mindfulness-based principles can be incorporated via helping individuals to pay attention to their internal experiences (e.g., thoughts and emotions) and their potential role in relapse and practice in incorporating mindfulness practices into daily life (Bowen et al. Subst Abus. 2009;30(4):295-305).

[354] In embodiments, the disclosed methods employ one or more elements of mindfulness skills, for example, in mindfulness-based relapse prevention, or otherwise employ mindfulness-based principles or mindfulness practices, including for purposes of relapse prevention, or to provide or support one or more other therapeutic effects, including: (a) a reduction of substance use, (b) a reduction of substance cravings, (c) a promotion of substance use abstinence, (d) a prevention of relapse into substance use, or (e) an improvement of at least one symptom of substance use disorder. In embodiments, a therapeutic effect may be shown by one or more of: (a) an increase in quality of life, (b) an increase in psychosocial functioning, (c) a decrease in use or frequency of a prescription medication, (d) a decrease in use or frequency of a recreational drug, (e) a decrease in obsessive compulsive thoughts, (f) a decrease in suicidality, (g) an increase in feelings of empathy, or (h) an increase in self-compassion. In embodiments, a therapeutic effect may be shown by one or more of: a reduction in the frequency of a compulsive or problematic behavior, a reduction in drive or urge to engage in a compulsive or problematic behavior, prolonged abstinence from a compulsive or problematic behavior, a prevention of relapse into a compulsive or problematic behavior, a reduction in severity of symptoms of a compulsive or problematic behavior, a reduction in the time spent on a compulsive or problematic behavior, an increase in quality of life, including subjective sleep, and an increase in psychosocial functioning.

[355] In embodiments, the disclosed methods employ motivational interviewing (Ml), a technique used to enhance motivation to change behavior that is widely used in addiction services. Miller & Rollnick (1991) describe a key element of this process as coming alongside the individual to explore ambivalence and elicit the person’s own ideas about change (Miller & Rollnick. Motivational interviewing: Preparing people to change addictive behavior. The Guilford Press; 1991)

[356] Motivational interviewing is characterized by therapists’ unconditional acceptance of where the individual finds themselves and their perspective. In motivational interviewing, a therapist’s role is to work in partnership and collaboration (not to act as the expert, to lecture or argue), to be genuinely curious and ask questions that provide opportunities for the individual to hear themselves talk about change, and to have compassion for the individual (to prioritize their needs and have an authentic regard fortheir well-being).

[357] In embodiments, the method comprises a therapy disclosed in, or based on a therapy disclosed in, with modifications known to those of ordinary skill based on the teachings herein, Applicant’s U.S. App. Nos. 18 / 291,057 or 18 / 563,857, both of which are incorporated by reference as if fully set forth herein.

[358] In embodiments, the method further comprises a post-treatment assessment of the subject’s SUD. This may be referred to herein as a follow-up phase. In embodiments, the follow up phase comprises evaluating the effects of a disclosed method on the subject’s SUD. Suitable assessment techniques and tools are described herein or are otherwise known to one of skill, and may comprise the same assessment techniques used in the baseline phase. In embodiments, the follow-up phase comprises an interview. In embodiments, the interview takes place 2 weeks after a subject completes the treatment phase.

[359] In embodiments, the method further comprises ongoing support following the treatment phase. For example, a subject may continue psychotherapy sessions, take adjunct medications, or both. In embodiments, a subject continues psychotherapy. In embodiments, the psychotherapy is group psychotherapy (e.g., group-talk therapy, 12-step programs, group counseling). In embodiments, a subject takes adjunct medication. In embodiments, the adjunct medication is naltrexone, buprenorphine, buprenorphine-naloxone, disulfiram, or naloxone. In embodiments, a subject continues psychotherapy and takes an adjunct medication.

[360] In embodiments, a subject receives ongoing support following the treatment phase for 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or more than 1 year, including times and ranges in between. WO 2025 / 160483                                   PCT / US2025 / 013057 G. Outcome Measures

[361] In embodiments, measures of therapeutic effect include any outcome measure, endpoint, effect measure, or measure of effect within clinical or medical practice or research which is used to assess the effect, both positive and negative, of an intervention or treatment, whether subject-reported (e.g., questionnaires, subject testimonies, etc.), based on other subject data (e.g., subject monitoring), gathered through laboratory tests such as blood work, urine samples, etc., through medical examination by a doctor or other healthcare professional, or by digital tools or means (e.g., electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps).

[362] The term “outcome measure” refers to data collected that is related to an improvement in an SUD in a subject. The outcome measure may include one or more physiological measures, one or more patient-centered outcomes (PCOMs), or one or more behavioral factor measures.

[363] A measure may be a physiological measure. A physiological measure monitors the physical reaction of a subject (e.g., drug or biomarker concentration in blood or plasma). A measure may be a PCOM. A PCOM is an assessment of the subject’s beliefs, opinions, and needs in relation to their treatment (e.g., subject-reported negative or positive effects relating to improvements in an SUD). A measure may be a behavioral factor measure. A behavioral factor measure is a measure of specific behaviors of the subject (e.g., quantity of alcohol consumed per day).

[364] A measure may be an improvement in psychological state. “Psychological state” refers to the condition or state of one’s mind including, but limited to, its physiological and subjective characteristics. In embodiments, psychological state is synonymous with the terms or phrases “mental condition,” “mental state,” “psychological condition,” “neural status,” “cognitive state,” “state of mind,” “frame of mind,” “emotional state,” etc. Physiologically, in the context hereof, psychological state broadly refers to the condition of the nervous system. Regardless, the effect, or improvement, may be prophylactic in terms of completely or partially preventing a disorder or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disorder, an adverse effect attributable to the disorder, and / or a comorbidity simultaneously present with the disorder.

[365] In embodiments, an outcome measure is a primary or a secondary outcome measure. “Primary outcome measure” refers to an outcome measure of greater relative importance, such as specified in a protocol. “Secondary outcome measure” refers to an outcome measure which may be more exploratory in nature, or for which effects may be too small to detect, but which are still of interest or valuable to assess. Because what is a “primary” as opposed to a “secondary” outcome measure may depend on circumstances and the goal(s) of a clinician or researcher, as well as a consideration of the totality of outcome measures used together for a particular purpose, reference herein to outcome measures as “primary” or “secondary” is suggestive only, and all outcome measures may be generally used and referred to as “outcome measures.”

[366] In embodiments, an outcome may be measured by monitoring or self-monitoring of a subject. In embodiments, the result of a disclosed method is measured by monitoring the subject’s increased decentering. “Decentering” refers to a third-person (or observer) perspective on thoughts, emotions and sensations which can be viewed as a form of exposure to aversive internal experiences (Hayes et al. Acceptance and Commitment Therapy: An experiential approach to behavior change. Guilford Press; 1999). It is proposed that increased decentering promotes acceptance rather than avoidance of internal experiences, and in the context of addiction, allows habitual and rigid responses to triggers and cravings to be replaced with more flexible behavior, thereby reducing relapse risk.

[367] In embodiments, the result of a disclosed method is measured by monitoring the subject’s increased awe. “Awe” is characterized by perceived vastness and need for accommodation (i.e., something violates the individual’s understanding of the world. Awe is thought to promote diminished sense of self, and it has been suggested that downstream effects of extreme awe may provide a shift in perspective or insight. Awe can be where one’s perspective expands beyond themself.

[368] In embodiments, the result of a disclosed method is measured by monitoring the subject’s increased positive affect. In embodiments, the result of a disclosed method is measured by monitoring the subject’s decreased negative affect. “Affect” is both a trait and a state. “Positive affect” is characterized by joy and high levels of energy, concentration, enthusiasm, and alertness, whereas “negative affect” is characterized by distress, anger, contempt, and nervousness or fear (Plys & Desrichard. Front Psychol. 2020;11:334).

[369] In embodiments, the result of a disclosed method is measured by monitoring the subject’s decreased experiential avoidance. “Experiential avoidance” refers to the maladaptive tendency to avoid or escape aversive internal experiences and has been identified as a maintenance factor across psychological disorders, including substance dependency (Hayes et al. J Consult Clin Psychol. 1996;64(6):1152-1168; Chapman et al. J Ration Emot Cogn Behav Then 2011 ;29:35-52).

[370] In embodiments, the result of a disclosed method is measured by monitoring the subject’s increased frequency of mystical-type experiences. “Mystical-type experience” is a potential psychological mechanism to influence outcome in psychedelic therapy. It may include features such as oceanic boundlessness, ineffability, sacredness, ego dissolution, transcendence of time and space, and universal interconnectedness, which have been linked to symptom reduction and improved quality of life following psychedelic use. Personally meaningful insight may be elicited by mystical experience, and mystical experience may have a relationship to psychedelic therapy outcome as some studies have indicated a mystical experience may result in abrupt, substantial, and sustained changes in behavior and / or perception (Ko et al. Psychopharmacol. 2022; 13:doi10.3389).

[371] In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction of substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction of substance cravings. In embodiments, the result of a disclosed method is measured by monitoring the subject’s promotion of substance use abstinence. In embodiments, the result of a disclosed method is measured by monitoring the subject’s prevention of relapse into substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s improvement of at least one symptom of substance WO 2025 / 160483                                   PCT / US2025 / 013057 use disorder.

[372] In embodiments, the result of a disclosed method is measured by monitoring the subject’s increase in quality of life. In embodiments, the resultof a disclosed method is measured by monitoring the subject’s increase in psychosocial functioning. In embodiments, the result of a disclosed method is measured by monitoring the subject’s decrease in use or frequency of a prescription medication. In embodiments, the result of a disclosed method is measured by monitoring the subject’s decrease in use or frequency of a recreational drug. In embodiments, the result of a disclosed method is measured by monitoring the subject’s decrease in obsessive compulsive thoughts. In embodiments, the resultof a disclosed method is measured by monitoring the subject’s decrease in suicidality. In embodiments, the result of a disclosed method is measured by monitoring the subject’s increase in feelings of empathy. In embodiments, the result of a disclosed method is measured by monitoring the subject’s increase in self-compassion. In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction in the frequency of substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction in drive or urge to engage in substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s prolonged abstinence from substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction in severity of symptoms of substance use. In embodiments, the result of a disclosed method is measured by monitoring the subject’s reduction in the time spent on substance use.

[373] In embodiments, the result of a disclosed method is measured by monitoring the number or content of paper diaries submitted by a subject. In embodiments, the result of a disclosed method is measured by monitoring the number or content of Internet-based diaries submitted by a subject. In embodiments, the result of a disclosed method is measured by monitoring the scores on a survey taken by a subject. In embodiments, the result of a disclosed method is measured by monitoring an available database wherein a subject tracks any psychological factors experienced. In embodiments, the resultof a disclosed method is measured by monitoring use of current technology, such as smartphones with applications which track any improvements the subject experiences in connection with the SUD.

[374] In embodiments, the resultof a disclosed method is determined using an assessment. In embodiments, the assessment is any of the Severity of Alcohol Dependence Questionnaire (SADQ), the Mini International Neuropsychiatric Interview 5 (MINI 5), the Columbia Suicide Severity Rating Scale (C-SSRS), the Alcohol Dependence Syndrome section of the SCID-5-CT (Clinical Trials Version), the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7 (GAD-7), the Short Inventory of Problems for Alcohol (SIP), the Alcohol Timeline Follow Back (TLFB), the Clinical Institute Withdrawal Assessment for Alcohol—Revised Version (CIWA-Ar), the Penn Alcohol Craving Scale (PACS), the Obsessive Compulsive Drinking Scale (OCDS), the Pittsburgh Sleep Quality Index (PSQI), the Interpersonal reactivity Index (IRI), the Short Form (36) Health Survey (SF-36), the Self-Compassion Scale (SCS), and the Trauma History Questionnaire (THQ). In embodiments, the assessment is the Mystical Experience Questionnaire (MEQ-30), Client Experience WO 2025 / 160483                                   PCT / US2025 / 013057 Questionnaire (CEQ), Patient Medication Questionnaire (PMQ), the Persisting Effects questionnaire, Hallucinogen Rating Scale, or an Adverse Childhood Experience (ACE) questionnaire.

[375] In some embodiments, a disclosed method improves a subject’s total score on the Mystical Experience Questionnaire (MEQ-30). The MEQ-30 evaluates experiences of mystical nature, including a sense of unity and sacredness by focusing on core components of mystical experiences as identified in psychological literature: mystical experience, positive mood, transcendence of time and space, and ineffability. In some embodiments, the MEQ-30 consists of 30 items rated on a 6-point scale (e.g., 0 = ‘none at all,’ 1 = ‘so slight cannot decide,’ 2 = ‘slight,’ 3 = ‘moderate,’ 4 = ‘strong,’ and 5 = ‘extreme’). Generally, a ‘complete mystical experience’ is defined as scoring 60% or more on all four MEQ-30 subscales (Barrett et al. J Psychopharmacol. 2015;29(11):1182-1190). Without being bound by theory, higher MEQ-30 scores are generally positively correlated with subsequent therapeutic outcomes, as subjects who report more intense mystical or transcendent experiences tend to show greater improvements in mental health measures (e.g., reductions in addictive behaviors). Higher MEQ-30 scores often reflect a more complete or “peak” mystical experience, something that is hypothesized to be the driver of lasting improvements in mood, perspective, and behavior (Barrett, 2015).

[376] In some embodiments, a disclosed method improves a subject’s total score on the MEQ-30 by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or greater than 10 points. In some embodiments, a disclosed method improves a subject’s total score on the MEQ-30 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between. In some embodiments, a disclosed method increases the frequency of a subject experiencing a ‘complete mystical experience.’

[377] In some embodiments, a disclosed method improves a subject’s mystical score on the MEQ-30. In some embodiments, a disclosed method improves a subject’s mystical score on the MEQ-30 by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or greater than 10 points. In some embodiments, a disclosed method improves a subject’s mystical score on the MEQ-30 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between. In some embodiments, a disclosed method improves a subject’s total mystical score on the MEQ-30 to 60% or greater, including 65%, 70%, 75%, 80%, 85%, 90%, 95%, and greater than 95%, including amounts and ranges in between.

[378] In some embodiments, a disclosed method improves a subject’s positive mood score on the MEQ-30. In some embodiments, a disclosed method improves a subject’s positive mood score on the MEQ-30 by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or greater than 10 points. In some embodiments, a disclosed method improves a subject’s positive mood score on the MEQ-30 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between. In some embodiments, a disclosed method improves a subject’s total positive mood score on the MEQ-30 to 60% or greater, including 65%, 70%, 75%, 80%, 85%, 90%, 95%, and greater than 95%, including amounts and ranges in between.

[379] In some embodiments, a disclosed method improves a subject’s transcendence of time and space score (“transcendence score”) on the MEQ-30. In some embodiments, a disclosed method improves a subject’s transcendence score on the MEQ-30 by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or greater than 10 points. In some embodiments, a disclosed method improves a subject’s transcendence score on the MEQ-30 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between. In some embodiments, a disclosed method improves a subject’s total transcendence score on the MEQ-30 to 60% or greater, including 65%, 70%, 75%, 80%, 85%, 90%, 95%, and greater than 95%, including amounts and ranges in between.

[380] In some embodiments, a disclosed method improves a subject’s ineffability score on the MEQ-30. In some embodiments, a disclosed method improves a subject’s ineffability score on the MEQ-30 by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or greater than 10 points. In some embodiments, a disclosed method improves a subject’s ineffability score on the MEQ-30 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between. In some embodiments, a disclosed method improves a subject’s total ineffability score on the MEQ-30 to 60% or greater, including 65%, 70%, 75%, 80%, 85%, 90%, 95%, and greater than 95%, including amounts and ranges in between.

[381] In some embodiments, a disclosed method improves a subject’s perspective and self-perception. In embodiments, a subject’s perspective and self-perception are related to a subject’s abusing or over-using of a substance (e.g., alcohol or opioids). In some embodiments, a disclosed method results in any of increased feelings of self-love, self-praise, self-compassion, self-complementing, self-encouragement, positive selfaffirmations, increased sense of confidence, increased mindfulness, and reduced excuses for maladaptive behaviors.

[382] In some embodiments, a disclosed method decreases experiential avoidance in a subject. In some embodiments, a disclosed method decreases experiential avoidance in a subject by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between.

[383] In some embodiments, a disclosed method increases decentering in a subject. In some embodiments, a disclosed method increases decentering in a subject by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%, including amounts and ranges in between.

[384] In embodiments, a disclosed method improves a subject’s quality of life. A subject may complete one or more questionnaires about quality of life, including, for example, the Wheel of Life questionnaire, the Life Effectiveness (LEQ-H) questionnaire, the 36-ltem Short Form Health Survey (SF-36), and the Quality of Life Scale (QOLS). In embodiments, a subject’s quality of life is improved by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the subject's baseline quality of life (e.g., their quality of life prior to the disclosed methods). WO 2025 / 160483                                   PCT / US2025 / 013057 i. Alcohol Use Disorder (AUD)

[385] In embodiments, the outcome measure is a change in a subject’s AUDIT score. In embodiments, a disclosed method results in the reduction of a subject’s AUDIT score b y 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, or greater than 20 points. In embodiments, a disclosed method results in a reduction of a subject’s AUDIT score to a score no longer considered indicative of high risk drinking (e.g., AUDIT score of 8-15). In embodiments, a disclosed method results in a reduction of a subject’s AUDIT score to a score no longer considered indicative of hazardous drinking (e.g., AUDIT score of 16-19).

[386] In embodiments, the outcome measure is a change in a subject’s AUD symptoms as assessed using the SCID-5 Alcohol Use Disorder Screener. In embodiments, a disclosed method results in the subject having a decreased number of AUD symptoms, assessed using the SCID-5 Alcohol Use Disorder Screener, compared to before the subject received treatment according to a disclosed method. In embodiments, the number of AUD symptoms is decreased by one, two, three, four, five, or at least five.

[387] In embodiments, a disclosed method results in a reduction in a subject’s number of daily drinks, e.g., as compared to their average number of daily drinks during a baseline phase (i.e., number of daily drinks prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject’s average number of daily drinks decreasing by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 drinks. In embodiments, a disclosed method results in maintaining a subject’s detoxification period from alcohol (e.g., the subject continues to abstain from alcohol).

[388] In embodiments, a disclosed method results in an increase in the number of days over a defined time period in which a subject does not drink alcohol (i.e., abstinent days), e.g., as compared to their drinking patterns during a baseline phase (i.e., drinking patterns prior to administration of a disclosed method). In embodiments, a disclosed method results in maintaining a subject’s detoxification from alcohol (e.g., the subject continues to abstain from alcohol). In embodiments, a disclosed method results in a subject abstaining from drinking for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject abstaining from drinking for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from drinking at least 1 year.

[389] In embodiments, a disclosed method results in an increase in the number of days over a defined time period in which a subject does not experience cravings to drink alcohol (i.e., abstinent days), e.g., as compared to their craving patterns during a baseline phase (i.e., craving patterns prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject abstaining from drinking for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject abstaining from drinking for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining WO 2025 / 160483                                   PCT / US2025 / 013057 from drinking at least 1 year.

[390] In embodiments, a disclosed method results in an increase in the number of days over a defined time period in which a subject promotes abstinence from drinking alcohol (i.e., abstinent days), e.g., as compared to their drinking patterns during a baseline phase (i.e., number of abstinent days prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject abstaining from drinking for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject abstaining from drinking for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from drinking at least 1 year.

[391] In embodiments, a disclosed method results in a decrease in the number of symptoms over a defined time period in which a subject experiences a symptom of AUD, e.g., as compared to the number of symptoms experienced during a baseline phase (i.e., number of symptoms prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject experiencing fewer symptoms of AUD for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject experiencing fewer symptoms of AUD for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from drinking at least 1 year.

[392] In some embodiments, a disclosed method results in an improvement in the severity of at least one symptom over a defined time period in which a subject experiences a symptom of AUD, e.g., as compared to the severity of symptoms experienced during a baseline phase (i.e., severity of symptoms prior to administration of a disclosed method). In embodiments, the improvement is a reduction in at least one symptom of AUD. In embodiments, the improvement is an elimination of at least one symptom of AUD. In embodiments, the reduction is compared to a baseline determination made before such disclosed methods. In embodiments, the improvement is durable, e.g., lasts for at least 3 months, 6 months, 9 months, 1 year, or greater than 1 year. ii. Opioid Use Disorder (OUD)

[393] In embodiments, the outcome measure is a change in a subject’s OUD symptoms as assessed using the Patient Medication Questionnaire (PMQ). In embodiments, a disclosed method results in the subject having a decreased score, assessed using the Patient Medication Questionnaire (PMQ), compared to before the subject was subjected to a disclosed method. In embodiments, for example, the subject’s PMQ score is decreased by 1, 2, 3,4, 5, or more than 5.

[394] In embodiments, a disclosed method results in an increase in the number of days over a defined time period in which a subject does not use opioids (i.e., abstinent days), e.g., as compared to their substance use patterns during a baseline phase (i.e., opioid use patterns prior to administration of a disclosed method). In embodiments, a disclosed method results in maintaining a subject’s detoxification from opioids (e.g., the subject continues to abstain from opioids). In embodiments, a disclosed method results in a subject abstaining from WO 2025 / 160483                                   PCT / US2025 / 013057 opioids for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject abstaining from opioids for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from opioid use for at least 90 days.

[395] In embodiments, a disclosed method results in an increase in the number of days over a defined time period in which a subject does not experience cravings to use opioids (i.e., abstinent days), e.g., as compared to their opioid craving patterns during a baseline phase (i.e., craving patterns prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject abstaining from opioids for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject abstaining from opioid use for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from opioid use for at least 90 days.

[396] In embodiments, a disclosed method results in a decrease in the number of symptoms over a defined time period in which a subject experiences a symptom of OLID, e.g., as compared to the number of symptoms experienced during a baseline phase (i.e., number of symptoms prior to administration of a disclosed method). In embodiments, a disclosed method results in a subject experiencing fewer symptoms of OLID for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In embodiments, a disclosed method results in a subject experiencing fewer symptoms of OLID for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In embodiments, a disclosed method results in a subject abstaining from opioid use for at least 90 days.

[397] In some embodiments, a disclosed method results in an improvement in the severity of at least one symptom over a defined time period in which a subject experiences a symptom of AUD, e.g., as compared to the severity of symptoms experienced during a baseline phase (i.e., severity of symptoms prior to administration of a disclosed method). In embodiments, the improvement is a reduction in at least one symptom of OUD. In embodiments, the improvement is an elimination of at least one symptom of OUD. In embodiments, the reduction is compared to a baseline determination made before such disclosed methods. In embodiments, the improvement is durable, e.g., lasts for at least 3 months, 6 months, 9 months, 1 year, or greater than 1 year.

[398] Other methods for assessing results of outcome measures, useful in the practice of the disclosed methods, will be known to those of skill in view of the teachings herein and the general knowledge in the art. H. Dose and Dosage

[399] In embodiments, a subject is administered a therapeutically effective amount of a compound, such as ketamine or esketamine, including as a disclosed composition, such as an esketamine OTF.

[400] Administration of a compound (or a compositions thereof) in an “effective amount,” a “therapeutically effective amount,” a “therapeutically effective dose,” or a “pharmacologically effective amount,” refers to an amount sufficient to provide a desired therapeutic effect, for example, relieving to an extent one or more of the symptoms of an SUD, or as otherwise disclosed. The result can be reduction and / or alleviation of the symptoms or causes of an SUD, or any other desired alteration of a biological system. An effective amount includes, in embodiments, a prophylactically effective amount. As it relates to the disclosure, “therapeutically effective amount,” refers to the amount of a compound of the disclosure (e.g., esketamine) sufficient to effect treatment when administered to a subject in need of such treatment. Administration of a compound or composition to a subject in a “therapeutically effective amount” or an “effective amount” means administration of an amount thereof in a manner as disclosed herein, sufficient to achieve the desired effect.

[401] In embodiments, a method comprises administering a therapeutically effective amount of esketamine.

[402] In embodiments, esketamine is administered in a total dose of about 115.3 mg.

[403] In embodiments, esketamine is administered in a total dose of about 172.95 mg.

[404] In embodiments, esketamine is administered in a total dose of about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, or about 250 mg, as well as amounts between these values, less than 130 mg, and greater than 250 mg.

[405] For each of the dose amounts above, reference to the specific integer amount will include further specific decimal amounts, for example reference to “172 mg” will be understood to include 172.05 mg, 172.10 mg, 172.15 mg, 172.20 mg, 172.25 mg, 172.30 mg, 172.35 mg, 172.40 mg, 172.45 mg, 172.50 mg, 172.55 mg, 172.60 mg, 172.65 mg, 172.70 mg, 172.75 mg, 172.80 mg, 172.85 mg, 172.90 mg, and 172.95 mg.

[406] In embodiments, esketamine is administered in a total dose of at least 150 mg, at least 151 mg, at least 152 mg, at least 153 mg, at least 154 mg, at least 155 mg, at least 156 mg, at least 157 mg, at least 158 mg, at least 159 mg, at least 160 mg, at least 161 mg, at least 162 mg, at least 163 mg, at least 164 mg, at least 165 mg, at least 166 mg, at least 167 mg, at least 168 mg, at least 169 mg, at least 170 mg, at least 171 mg, at least 172 mg, at least 172.95 mg, at least 173 mg, at least 174 mg, at least 175 mg, at least 176 mg, at least 177 mg, at least 178 mg, at least 179 mg, at least 180 mg, at least 181 mg, at least 181 mg, at least 183 mg, at least 184 mg, at least 185 mg, at least 186 mg, at least 187 mg, at least 188 mg, at least 189 mg, at least 190 mg, at least 191 mg, at least 192 mg, at least 193 mg, at least 194 mg, at least 195 mg, at least 196 mg, at least 197 mg, at least 198 mg, at least 199 mg, at least 200 mg, at least 205 mg, at least 210 mg, at least 215 mg, at least 220 mg, at least 225 mg, at least 230 mg, at least 235 mg, at least 240 mg, or at least 250 mg, as well as amounts between these values. In embodiments, wherein a disclosed composition includes esketamine, it will be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) e.g., not at least 200 mg, not at least 205 mg, not at least 210 mg, not at least 215 mg, not at least 220 mg, not at least 225 mg, not at least 230 mg, not at least 235 mg, not at least 240 mg, not at least 245 mg, or not at least 250 mg.

[407] In embodiments, esketamine is administered in a total dose of 225 mg or less, 220 mg or less, 215 mg or less, 210 mg or less, 205 mg or less, 200 mg or less, 195 mg or less, 190 mg or less, 185 mg or less, 180 mg or less, 179 mg or less, 178 mg or less, 177 mg or less, 176 mg or less, 175 mg or less, 174 mg or less, 173 mg or less, 172.95 or less, 171 mg or less, 170 mg or less, 169 mg or less, 168 mg or less, 167 mg or less, 166 mg or less, 165 mg or less, 164 mg or less, 163 mg or less, 162 mg or less, 161 mg or less, 160 mg or less, 159 mg or less, 158 mg or less, 157 mg or less, 156 mg or less, 155 mg or less, 154 mg or less, 153 mg or less, 152 mg or less, 151 mg or less, 150 mg or less, 149 mg or less, 148 mg or less, 147 mg or less 146 mg or less, 145 mg or less, 144 mg or less, 143 mg or less, 142 mg or less, 141 mg or less, 140 mg or less, 135 mg or less, or 130 mg or less, as well as amounts between these values. In embodiments, esketamine is administered in a total dose of 130 mg or less, 120 mg or less, 110 mg or less, 100 mg or less, 90 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, or 10 mg or less (including a dose of 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg), as well as amounts between these values.

[408] In embodiments, esketamine is administered in a dose of between about 100 mg and about 200 mg, between about 100 mg and about 125 mg, between about 125 mg and about 150 mg, between about 150 mg and about 175 mg, or between about 175 mg and about 200 mg.

[409] In embodiments, esketamine is administered in a dose of between about 110 mg and about 120 mg, or between about 170 mg and about 180 mg. In embodiments, esketamine is administered in a dose of between about 110 and 120 mg. In embodiments, esketamine is administered in a dose of between about 110 and 115 mg. In embodiments, esketamine is administered in a dose of about 115.3 mg.

[410] In embodiments, esketamine is administered in a total dose of about 130 mg to 170 mg, about 135 mg to 165 mg, about 140 mg to 160 mg, about 145 mg to 155 mg, about 146 mg to 154 mg, about 147 mg to 153 mg, about 148 mg to 152 mg, about 149 mg to 151 mg, or about 150 mg.

[411] In embodiments, esketamine is administered in a total dose of about 150 mg to 190 mg, about 155 mg to 185 mg, about 160 mg to 180 mg, about 165 mg to 175 mg, about 170 to 176 mg, about 171 mg to 175 mg, about 172 mg to 174 mg, or about 172.95 mg.

[412] In embodiments, esketamine is administered in a dose of between about 140 and 160 mg. In embodiments, esketamine is administered in a dose of between about 145 and 155 mg. In embodiments, WO 2025 / 160483                                   PCT / US2025 / 013057 esketamine is administered in a dose of between about 165 and 175 mg. esketamine is administered in a dose of between about 170 and 175 mg. In embodiments, esketamine is administered in a dose of between about 171 and 174 mg. In embodiments, esketamine is administered in a dose of about 172.95 mg.

[413] Where an active agent, such as esketamine, is administered as a composition, e.g., as an esketamine OTF, the compound may be present in the composition in an amount so that a single dose is (whether or not the dose is provided as a single unit dosage form) any of the dose amounts herein. Accordingly, it will be understood that the milligram amount of the composition will be greater than the milligram amount of the active agent, including for example if the active agent is provided in a salt form.

[414] In embodiments, the total dose amount may be divided among multiple dosage forms. For example, in embodiments, an esketamine OTF comprises 57.65 mg of esketamine. Accordingly, administration includes a single esketamine OTF (57.65 mg of esketamine), two esketamine OTFs (115.3 mg of esketamine), three esketamine OTFs (172.95 mg of esketamine), and four esketamine OTFs (230.6 mg of esketamine).

[415] Any of the above dose amounts of esketamine may be administered as 1 dosage form, or may be divided among multiple dosage forms, such as 2 dosage forms, 3 dosage forms, 4 dosage forms, or greater than 4 dosage forms. In embodiments, esketamine is administered as 1 dosage form. In embodiments, esketamine is administered as 2 dosage forms. In embodiments, esketamine is administered as 3 dosage forms. Each individual dosage form may be between 25 mg and 150 mg (e.g., 25 mg to 125 mg, 25 mg to 100 mg, 25 to 75 mg, and 25 to 50 mg), between 30 mg to 70 mg, between 35 mg to 65 mg, between 40 mg to 60 mg, between 45 mg to 55 mg, about 55 mg, about 50 mg, or 57.65 mg.

[416] In embodiments, the dosage form is an oral transmucosal dosage form, such as any disclosed herein.

[417] In embodiments, esketamine is administered in a mg dosage amount based on the kg weight of the subject of, e.g., about 1.4 mg / kg, about 1.3 mg / kg, about 1.2 mg / kg, about 1.1 mg / kg, about 1.0 mg / kg, about 0.9 mg / kg, about 0.8 mg / kg, about 0.7 mg / kg, about 0.6 mg / kg, about 0.5 mg / kg, about 0.4 mg / kg, about 0.3 mg / kg, about 0.2 mg / kg, or about 0.1 mg / kg. In embodiments, esketamine is administered in a mg dosage amount based on the kg weight of the subject of, e.g., less than 1.4 mg / kg, less than 1.3 mg / kg, less than 1.2 mg / kg, less than 1.1 mg / kg, less than 1.0 mg / kg, less than 0.9 mg / kg, less than 0.8 mg / kg, less than 0.7 mg / kg, less than 0.6 mg / kg, less than 0.5 mg / kg, less than 0.4 mg / kg, less than 0.3 mg / kg, less than 0.2 mg / kg, or less than 0.1 mg / kg. In embodiments, esketamine is administered in a mg dosage amount based on the kg weight of the subject of, e.g., greater than 0.1 mg / kg, greater than 0.2 mg / kg, greater than 0.3 mg / kg, greater than 0.4 mg / kg, greater than 0.5 mg / kg, greater than 0.6 mg / kg, greater than 0.7 mg / kg, greater than 0.8 mg / kg, greater than 0.9 mg / kg, greater than 1.0 mg / kg, greater than 1.1 mg / kg, greater than 1.2 mg / kg, greater than 1.3 mg / kg, or greater than 1.4 mg / kg.

[418] In embodiments where an additional active agent is administered, the agent may be administered in any amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., less than 25 mg (including a dose of about 10 mg, about 5 mg, about 1 mg, and about 0.5 mg), about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, and greater than 250 mg, including greater than 500 mg, 1 g, and 2 g, as well as amounts between these values.

[419] In embodiments, administration of esketamine according to a disclosed oral transmucosal dosage form, such as an esketamine OTF, results in a bioavailability of esketamine of at least 15%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 35%, or at least 40%. In embodiments, the bioavailability of esketamine is at least 25%. In embodiments, administration of esketamine according to a disclosed oral transmucosal dosage form, such as an esketamine OTF, results in a bioavailability of esketamine of about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, or about 40%. “Bioavailability,” in such examples, refers to the proportion of esketamine administered in the oral transmucosal dosage form that reaches systemic circulation in its active form.

[420] In embodiments, administration of esketamine according to a disclosed oral transmucosal dosage form, such as an esketamine OTF, results in an amount of esketamine that reaches systemic circulation in its active form of about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In embodiments, administration of esketamine according to a disclosed oral transmucosal dosage form, such as an esketamine OTF, results in an amount of esketamine that reaches systemic circulation in its active form of at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg.

[421] In embodiments, administering esketamine according to a disclosed method results in a maximum plasma concentration (Cmax) of greater than about 90 ng / mL, 100 ng / mL, 110 ng / mL, 120 ng / mL, 130 ng / mL, 140 ng / mL, 150 ng / mL, 160 ng / mL, 170 ng / mL, 180 ng / mL, 190 ng / mL, 200 ng / mL, 210 ng / mL, 220 ng / mL, 230 ng / mL, 240 ng / mL, or 250 ng / mL. In embodiments, the Cmax is between about 150 ng / mL and 250 ng / mL. In embodiments, the Cmax is between about 180 ng / mL and 220 ng / mL. For instance, Example 3 describes a pharmacokinetic study of an exemplary esketamine OTF administered via the oral transmucosal route.

[422] In embodiments, administering esketamine according to a disclosed method results in a time of Cmax (Tmax) of between about 1 and 30 minutes. In embodiments, the Tmax is between about 10 and 30 minutes. In embodiments, the Tmax is between about 15 and 25 minutes. In embodiments, the Tmax is about 20 minutes.

[423] Although exemplary dose amounts are provided for esketamine, one of skill will appreciate that in alternative embodiments, methods comprise the administration of other compounds to a subject (e.g., ketamine, WO 2025 / 160483                                   PCT / US2025 / 013057 other NMDA antagonists, other disclosed compounds), and such administration will be at dose amounts appreciated by one of skill, such as by applying the dose amounts above, or those known in the art.

[424] Also provided herein are schedules for dosing, i.e., “dosing schedules” for the administration of different dose amounts, including with variation in both the dose and the dosage overtime. Herein, a “dosing schedule” and a “dosing regimen” are used interchangeably.

[425] In exemplary dosing schedules, a subject is administered an effective dose of esketamine on a set, repeating schedule, where the subject is administered an effective dose of the esketamine every other day, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or more than every 7 days.

[426] In embodiments, a dosing schedule continues in one pattern for a specific duration of time, including 1-7 days, and greater than 7 days, including 14, 21, 28, 29, 30, 31, 35, 42, 49, 60, 75, 90, or 120 days. In embodiments, the frequency of dosing and duration of elapsed time between administrations depends on the agent administered and the disorder to be treated, but will be understood by one of skill in view hereof.

[427] It will be understood that a therapeutically effective amount can vary from subject to subject, such as due to variation in the metabolism of the active agent, in the age, weight, pharmacogenomics, and general condition of the subject, the condition being treated, the severity of the condition being treated, the manner of administration, the judgment of the prescribing physician, and the like, all of which can be determined by one of skill in view of the teachings herein and the knowledge in the art.

[428] In embodiments, the disclosed pharmaceutical compounds and compositions are administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual subject and the severity of the underlying disease, the subject’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Dosage levels thus may differ from subject to subject, for individual subjects across time, and for different pharmaceutical compositions and formulations, but shall be able to be determined with ordinary skill.

[429] Determination of appropriate dosing shall include not only the determination of single dosage amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) preferable for administration. Dose and dosage may vary depending upon the onset, progression, severity, frequency, duration, probability of, or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional, or local side effects, the presence of other disorders or diseases in the subject, and other factors appreciated by those in the art (e.g., medical or familial history). Dose amount, frequency, or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the disorder or symptoms, any adverse side effects of the treatment or therapy, or concomitant medications. Those in the art will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect, and to do so depending WO 2025 / 160483                                   PCT / US2025 / 013057 on the type of therapeutic effect desired and to avoid or minimize adverse effects.

[430] In embodiments, the dose administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the route of administration, the composition administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like, and therefore any dosage amounts or ranges described are not intended to limit the scope of the disclosure. I. Examples

[431] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure, which shall be known by reference to the complete disclosure and appended claims. EXAMPLE 1. Mixed Methods Single-Case Experiment Exploring KAP in Harmful Drinkers

[432] Mixed Methods Design. The example is a mixed methods single-case experiment exploring potential mechanisms of ketamine-assisted psychotherapy (KAP) in harmful drinkers. The quantitative element of the study used a multiple baseline AB design with extended follow-up to test the effect of a disclosed method comprising esketamine-assisted MBRP on decentering, experiential avoidance, and alcohol-related outcomes in four hazardous drinkers. Participants completed daily self-report measures during the 50 days of the two phases of the study: a variable baseline phase which introduced the therapist support to reduce alcohol use over four 60-minute telephone calls (A), followed by an intervention phase (B) when participants received the seven-session treatment over four weeks followed by a period of daily follow-up (FIG. 1). Hypotheses were tested using randomisation tests and analysis of non-overlapping pairs to evaluate both individual and aggregated effect sizes between baseline (A), and treatment (B) phase.

[433] Participants. A total of eight potential participants were screened for eligibility as hazardous drinkers after expressing interest in participating in a larger ketamine assisted MBRP trial. Five participants enrolled in the study with one individual excluded at initial screening for presence of severe AUD diagnosis and another participant later withdrew after the first ketamine experience. At the pre-screening telephone call, potential participants were required to be over 18 and currently meet the criteria for hazardous drinking status (described below) and display a desire to address their relationship to alcohol.

[434] After initial eligibility was assessed, participants were invited for a medical in-person screening at the research clinic and excluded if they: a) held or met criteria for a diagnosis of severe alcohol use disorder; b) had uncontrolled hypertension or other contraindicated medical condition; orc) had a history of or family history of severe mental illness. Four eligible participants provided informed consent at the medical screening and completed the study by attending all seven psychotherapy sessions. Participants ended their participation with a semi-structured interview to gauge their experience of the treatment and were reimbursed with £70 of shopping vouchers. All procedures and participant visits took place at the Psychopharmacology and Addiction Research Centre (PARC) and Nutrition and Physiology Research Unit (NPRU) research facilities at the University of Exeter. Ethical approval was granted by the School of Psychology Ethics board.

[435] Determination of Sample Size. Following Kratochwill et al, (2010) who suggest that five data points per WO 2025 / 160483                                   PCT / US2025 / 013057 phase (e.g. baseline, treatment phase) across four participants are needed to meet the power standards, a sample of 8 was originally determined to allow for a 50% drop-out rate (Kratochwill et al. Single-case designs technical documentation. What works clearinghouse; 2010). Due to time constraints and unforeseen difficulties in study start up, recruitment stopped after 4 participants had completed the study.

[436] Measures and Methods

[437] Screening Measures. The Alcohol Use Disorders Identification Test (AUDIT) (Reinert & Allen. Alcohol Clin Exp Res. 2002; 26(2):272-279). The AUDIT is a reliable tool developed by the World Health Organization for detecting hazardous drinking and alcohol use disorders. It consists of 10 questions that assess alcohol consumption, drinking behaviors, and alcohol-related issues. Hazardous drinking is typically indicated by an AUDIT score range of 8-15 (Babor et al. AUDIT-The Alcohol Use Disorders Identification Test: Guidelines for Use in Primary Heath Care. 2nd ed. 2001). This was used to gauge severity of hazardous drinking in participants.

[438] SCID-5 Alcohol Use Disorder Screener. This short semi-structured interview assesses alcohol use with 12 questions that identify symptoms of AUD. It has been shown to have good reliability and validity for screening AUD symptoms (American Psychiatric Association [APA], 2000). The presence of 6 or more symptoms indicates severe AUD. Therefore, participants were required to score lower than 6 to be eligible.

[439] Psychosis risk screening Questionnaire — Brief Version (PQ-B: Loewy et al. Schizophr Res. 2011; 129(1 ):42-46). This screening measure assesses for symptoms indicating risk for psychosis. The 21 item questionnaire has been shown to have adequate reliability and validity for screening symptoms of psychosis. The presence of 6 or more symptoms indicates the presence of psychosis. To meet the exclusion criteria of history of psychosis, participants were required to deny a personal or family history of psychosis and score lower than 6 the PQ-B to be deemed eligible.

[440] Primary Outcome Measures. The following measures were created within Qualtrics survey platform and, to minimize reporting under the influence of alcohol, delivered to participants’ smartphones at 8am to be answered by reflecting on how they felt “in general on the previous day.” For consistency, all items were visual analogue scales 1-100.

[441] Decenterinq. The Metacognitive Processes of Decentering-State version (MPD-s) is a recently developed 3-item state measure of decentering (Hanley et al. Psychol Assess. 2020;32(10):956-971). This measure is based on a factor-analytic model of metacognition consisting of 1. meta-awareness (I was able to watch my thoughts, emotions, and sensations drift by like leaves on a stream) 2. (dis)identification from internal state ( / experienced myself as separate from my changing thoughts, emotions, and sensations) and 3. (non)reactivity to internal experience ( / was able to step back and be aware of distressing thoughts, emotions and sensations, without being taken over by them), and is sensitive to change after a short mindfulness exercise, and moreover, shown to mediate the effects of mindfulness on therapeutic outcomes (Hanley et al. Psychol Assess. 2020;32(10):956-971).

[442] Alcohol-related Experiential Avoidance. A one-item measure of experiential avoidance consistent with existing psychological flexibility measures (e.g., Luoma etal. Addict Res Theory. 2011;19(1 ):3-13) was created to relate to alcohol use: The urge to drink when I felt difficult emotions was: 0 (extremely low) -100 (extremely high). It is common practice in single-case designs to create single-item self-report measures relevant to the target outcome (cf. B. Thompson, 2021).)

[443] Secondary Outcome Measures. Affect. To measure affect, items from the well-validated Positive Affect (PA) and Negative Affect (NA) Schedule (PANAS: Watson and Tellegren, 1991) were selected based on their within-individual structure (Cooke et al. Psychol Assess. 2022;34(12):1126-1137). For NA, participants were asked to rate the extent to which they felt: 1. upset, 2. ashamed, 3. hostile, 4. nervous, and 5. afraid. For PA, the items were 1. inspired 2. active 3. determined 4. satisfied 5. calm. (0 - Not at all, 100- Most extreme)

[444] Alcohol Craving. A two-item measure was created to measure the daily intensity and frequency of alcohol cravings: 1. How intense were your cravings? (0-100) 2. How frequent were your cravings? (0-100).

[445] Awe. Following the awe self-report literature (e.g., Hendricks et al. Int Rev Psychiatry. 2018;30(4):331-342), as an approximate measure of daily awe, a single-item question was created: “to what extent did you feel a sense of awe?”

[446] Alcohol Follow-back Method. To monitor the frequency and degree of alcohol consumption throughout the study, participants entered if, and, if so, how many alcoholic drinks they had the previous day via Qualtrics or reported their alcohol consumption at each meeting with the therapist / researcher.

[447] Psychotherapy Treatment. Subjects received 7 total therapy sessions during the four week treatment phase, with a two-week follow up interview. “Follow-up” refers to the period following the last session of the ketamine-assisted psychotherapy course. The 7 therapy sessions, based on the manualized mindfulnessbased relapse prevention approach, aimed to assist participants in building a fulfilling life free from alcohol. Each 1.5-hour session covered a topic related to either relapse prevention or well-being promotion, interspersed with different relaxation or mindfulness exercises, with approximately half the therapeutic time dedicated to discussing what the participant felt was important.

[448] The sessions encompassed a variety of relapse prevention strategies, such as managing high-risk situations, activity scheduling, introducing new sources of positive reinforcement and cognitive-behavioral therapy (CBT)-based techniques to address thinking biases. Mindfulness-related practice, like urge surfing or stepping back from thoughts, were discussed in every session, and participants were encouraged to practice meditation and these skills in their spare time, although this was not monitored. Participants were also encouraged to contemplate the resources necessary for a meaningful life without alcohol. A therapy manual was transformed into a step-by-step guidebook for both the participant and therapist.

[449] Procedure. Baseline Phase. Once recruited, participants began completing daily measures via Qualtrics and received four 1-hour telephone calls spread across their individual baseline period. Among the objectives of this phase were for the therapists to: (a) assist participants reduce their drinking before treatment; WO 2025 / 160483                                   PCT / US2025 / 013057 (b) build rapport; and (c) come to a shared formulation of their drinking problem.

[450] Treatment Phase. After participants had completed their individual baseline phase, the treatment phase began. The treatment phase consisted of a ketamine dosing session followed by a therapy session on the subsequent day for three consecutive weeks. On the fourth and final week of treatment, participants attended a therapy session without a preceding ketamine dosing session.

[451] Ketamine Administration. On each of the participant’s three drug administration days, participants were required to fast before arriving at the research clinic. Before each dosing, the therapist prepared the subjects in a psychotherapy-type room by discussing current feelings and potential ketamine experiences, including intentions and expectations for the experience. Participants were encouraged to remain open and curious about whatever might arise during the experience. A therapist was present throughout the infusion to provide reassurance if needed.

[452] Upon arrival at the research clinic, participants' blood pressure and blood-alcohol levels were measured. The study physician then administered three oral thin film s-ketamine strips in total doses of 171 mg (3 OTF strips, 57 mg each). During the infusion, participants were situated in a single-bed hospital-type room and listened to ambient instrumental music through headphones. This setup was designed to foster relaxation and minimize distractions from external stimuli. Participants recovered from the acute experience after around 60 minutes, at which point they verbally described their experience to be audio-recorded for the qualitative analysis. The participant then stayed with the therapist for a further period, approximately 90 minutes, and provided psychological support until the participant was safe to travel home.

[453] Follow-up Interview. To supplement the case study material collected through note-taking on each participant’s therapeutic process, participants attended a 1 -hour audio-recorded follow-up interview two weeks after completing their final psychotherapy session. This gave participants an opportunity to describe their experiences in connection with the treatment and their personal reflections on the process.

[454] Data Analysis. As recommended by Bulte and Onghena (2008), Visual analysis (VA) and statistical analysis were performed. Analysis was conducted with the R statistical package. The median was chosen as the measure of central tendency due to its robustness against outliers. To perform trend analysis, the 'splitmiddle' technique was employed following recommendation (Bulte & Onghena. Behav Res Methods. 2008;40(2):467-478). This method is advantageous because it is less affected by outliers. However, for this analysis, any missing data filled with phase medians were excluded.

[455] To allow comparison of baseline and intervention means, Randomisation tests (RT) were performed. By using permutations of the data to create a distribution under the null hypothesis, RTs offer statistical inferences without relying on specific distributional assumptions (Heyvaert & Onghena. Neuropsychol Rehabil. 2014;24(3-4):507-527). The current study had 384,000 possible randomisation distributions. 1000 randomisation distributions were run using a Monte Carlo simulation (Morley, 2017). P-values were calculated by RTs and an alpha value of .05 was determined by dividing 1 by the number of measurements during the WO 2025 / 160483                                   PCT / US2025 / 013057 transition phase. RTs were executed based on the underlying assumption that each phase had at least 13 data points available for analysis. Effect sizes for each participant were computed by calculating non-overlap of all pairs (NAP; Parker & Vannest. Behav Ther. 2009;40(4):357-367), enabling an examination into the magnitude of the observed effect.

[456] Results. For brevity, brief text summaries are presented for each participant’s therapeutic journey alongside plots detailing their daily alcohol use throughout the study period. TABLE 1 below describes the participant’s screening data and history with other drugs, whereas TABLE 2 summarizes the initial individual formulations of the participants' hazardous drinking derived from the support calls of the baseline using the 5 P’s (presenting problem(s), predisposing factors, precipitating factors, perpetuating factors, protective factors) approach (Dudley & Kuyken. Case formulation in cognitive behavioral therapy: A principle-driven approach. Formulation in psychology and psychotherapy. Routledge; 2013). TABLE 1 Participant screening data and recreational drug history: Participant 1 Participant 2 Participant 3 Participant 4 SCID-Alcohol 5 4 5 4 AUDIT score 19 16 18 20 Psychosis Screen 2 0 0 0 Other Drugs Historic regular MDMA, cocaine LSD once Historic irregular cocaine, MDMA Occasional MDMA, cocaine Previous Ketamine Use Tried once before None None Occasional Recreational Use TABLE 2 Psychological formulations of each participant’s drinking problem: Participant 1 Participant 2 Participant 3 Participant 4 Age, Gender 51, F 53, M 46, F 41, F Presenting Problems 3-4 day solo binges per week, Unstable Emotions 5 beers every night, Chronic dysphoria Maintaining abstinence (3 months) despite chronic alcohol-seeking behavior to manage emotion Binge-drinking induced self-destructive behavior, C-PTSD symptoms Predisposing Factors Strict family environment Timid temperament Distant and Abusive Father (‘heavy drinker’) Rigid Temperament Distant and Neglectful Father (‘alcoholic’) Alcoholic parents, Chaotic family environment Physical abusive stepfather Domestic Violence Traumatized Mother, harsh critical parenting style Precipitating Factors Teenage Rebellion Drinking culture with family Binge-pattern learnt from 90's rave scene Drinking culture in family Habitually engrained behavior Drinking culture in family; Alcohol-based social network / drinking work culture; Parenthood combined with Pandemic Developed binge-pattern in adolescence Relied upon alcohol to cope with effects of long covid Perpetuating Factors Partner conflict -"to cope", unfulfilled Job / relationship Perfectionism Numbing effect of alcohol Isolated and narrow lifestyle Low-self-efficacy Reinforcing effects of alcohol Ability to hide drinking from family Loss of role (job) Unresolved trauma Associated with partner intimacy Long covid symptoms Reinforcing effects of alcohol Protective Factors (Partner?) Responsibility to Family, Perfectionism Family, Concern for Health Family Concern for Health, Sense of responsibility Function of Alcohol “to numb my feelings" "I enjoy it" / "relieve boredom" to cope “to have fun" "relieve social anxiety" “to punish myself’

[457] Participant 1 (“P1”). P1 expressed a desire to improve her relationship with alcohol rather than abstain. Her four support calls took place during a 13-day baseline phase (see FIG. 2). P1 attributed her difficulty in cutting down to abstinence during the support phase to a deterioration in her romantic relationship, leaving her ‘feeling trapped’. Between doses 1 and 2, P1 faced a ‘mini-crisis’ when she learned she was expected to take over the family business. This exacerbated feeling ‘being trapped’ and led to increased drinking but she persevered with the treatment. In her final ketamine session, P1 reported a death-like experience which she linked to her current trajectory: "That's where I'm going; I'm propelling myself towards an early grave." In the final psychotherapy session, P1 spoke of self-kindness, and making positive life changes, like initiating a new friendship and negotiating a reduced role in the family business. She expressed confidence in addressing her drinking problem, but only once she had addressed her relationship difficulties.

[458] Participant 2 (“P2”). P2 was clear that he felt that at least 6 months of abstinence was his goal for the treatment, having not had a period of abstinence for 13 years. At the time of assessment, he had a steady pattern of drinking 4-5 cans of lager every night. P2’s support calls took place during a 27-day baseline (see FIG. 3). P2 was strikingly more comfortable in describing his feelings following his first ketamine experience. Like P1, P2 described a death-like experience after his third experience, which evoked sadness and empathy for family members. P2 successfully cut down to abstinence prior to beginning treatment and maintained this throughout the life of the study.

[459] Participant 3 (“P3”). P3 had decided to pursue ketamine treatment to attempt abstinence and was clear that if she did not address the problem, she was at-risk of losing her family. Her baseline phase took place over 14 days (see FIG. 4). P3 described the main theme of her ketamine’s experience as of 'love and selfacceptance'. She described how previously the concept of self-love was only intellectual for her, and how she thought the ketamine experiences allowed her to feel love towards herself. P3 maintained abstinence throughout the study period.

[460] Participant 4 (“P4”). P4 had a 32-day baseline (see FIG. 5). P4 hoped the ketamine treatment could address the underlying reasons for her problematic relationship with alcohol and aimed to remain abstinent for 6 months before attempting to re-introduce alcohol use in a more controlled way. She reported more WO 2025 / 160483                                   PCT / US2025 / 013057 underwhelming ketamine experiences except for her final session which she described as “an amazing experience” which allowed a “stronger, fun part of [herself] to come out”. From the second for the baseline phase onwards she reported maintaining abstinence to the end of the study period.

[461] Quantitative Results. Four participants completed the 50-day study, providing at least 13 baseline data points. Missing data was minimal; there were four missing data points for participant 1 (P1), zero for P2, one for P3 and three for P4. Median phase values substituted missing data for VA and NAP calculations. In FIGS. 6-13, the y-axis depicts experiential avoidance (EA), the x-axis depicts number of days, the slanted line to the left of the vertical line depicts the baseline trend, the slanted line to the right of the vertical line depicts the intervention trend, the vertical line depicts the transition, and the horizontal lines depict the median levels of the baseline and intervention trends.

[462] Primary Hypothesis 1(a): Reduced Experiential Avoidance After Ketamine-Assisted MBRP

[463] Participant 1 (“P1”). FIG. 6 shows an unstable baseline marked by a downward trend, suggesting an effect of the baseline phase on EA. An immediate and sharp reduction in EA is visible at transition. This recovered but, overall, the median level is lower than baseline, and the trend line shows a slight upward trend, concluding the presence of an effect exists is difficult to make.

[464] Participant 2 (“P2”). FIG. 7 shows a relatively stable baseline marked by a downward trend. An immediate and sharp reduction in EA is visible at transition. This then recovered to baseline levels quickly before dropping sharply again. EA continued to decline more gradually, and this continued after the treatment. The difference between the trend lines suggests an effect, but the intervention phase trend gradient appears skewed by the instability immediately following the intervention's introduction. Overall, an effect of the intervention is illustrated but firm conclusions are limited by an apparent effect of the baseline.

[465] Participant 3 (“P3”). FIG. 8 shows an unstable baseline marked by a slight trend upwards for P3. This variability continued in the intervention, but the median level half that of the baseline phase illustrates an effect of the intervention with median, and a trend in the opposite direction with a steeper gradient suggests continued reduction in EA post-intervention. Notably, the effect of the intervention seemed delayed, denoted by a sharp reduction in EA 5 days post transition.

[466] Participant 4 (“P4”). FIG. 9 shows an unstable baseline marked by a downward trend, suggesting an effect of the baseline on EA. This variability continued in the intervention phase but there was an immediate spike following transition, inconsistent with the hypothesis. Moreover, P4's EA spiked again towards the end of the study, and therefore despite a large difference in median levels between phases, there is little evidence of an effect of the intervention for P4.

[467] Individual and Combined Randomization and Effect Size Tests. TABLE 3 shows the mean scores, nonoverlap of all pairs (NAP) effect sizes, and significance of each participants’ mean scores for each phase for EA. No randomisation test reached statistical significance and the NAP analysis returned negligible effect sizes (according to Parker, & Vannest, 2009) for all individual data and combined data. WO 2025 / 160483                                   PCT / US2025 / 013057 TABLE 3 Experiential avoidance scores: Phase Duration (days) Mean Score (SD) PPT A BA B NAP P Sig 1 13 37 73.1 (8.7) 60.3(12.1) 0.18 0.89 0.05 2 27 23 70.7 (6.5) 46.8 (9.4) 0.03 0.61 0.05 3 14 3658.4(18.1) 31.3(17.4) 0.19 0.69 0.05 4 32 18 62.3 (13.1) 14.2(11.2) 0.04 0.83 0.05 Combined 86 114 65.9 (11.3) 41.1 (9.7) 0.11 0.98 0.05

[468] Primary Hypothesis 1(b): Increased Decentering Following Ketamine- Assisted MBRP

[469] Participant 1 (“P1”). PTs baseline in FIG. 10 shows an upward trend, suggesting an effect of the baseline. The intervention phase is marked by instability. A minor difference in median levels across phases is visible as is a steep increase in decentering following transition. Of note, a pronounced, sustained increase in decentering is visible at the time point which marks PTs final ketamine experience (day 37). Given the discrepancy in upward trends between baseline and intervention, alongside only a slight difference in median level, it is hard to reach a conclusion on the presence of an effect for P1.

[470] Participant 2 (“P2”). FIG. 11 shows a stable baseline. Immediately following transition, decentering remains stable before displaying more variability and marked by an upward trend. Compared to baseline, there is no difference in median levels, but a difference is seen in trend, suggesting an effect of the intervention. Overall, there appears to be a delayed effect of the intervention in the predicted direction.

[471] Participant 3 (“P3”). FIG. 12 shows an unstable baseline marked by a trend upwards for P3. There seems to be a sharp increase in decentering following transition to intervention but this is difficult to interpret in the context of marked variability across phases. However, following P3's second ketamine experience (day 20) there is a large sharp increase in decentering which is mostly maintained, and although the trend appears similar across phases, an approximate 25% difference between median levels suggests the presence of an effect of the intervention.

[472] Participant 4 (“P4”). FIG. 13 shows decentering to remain fairly stable in baseline until the final days where it rises sharply, potentially reflecting the participant's reported practice of mindfulness to prepare for the intervention. The intervention phase is marked by substantial variability with decentering dropping sharply following transition. Comparing median levels, there appears to be an effect, but the pre-transition rise in decentering is reflected by similar trends across phases, limiting confidence in this conclusion.

[473] Individual and Combined Randomization and Effect Size Tests. TABLE 4 shows the mean scores, NAP effect sizes, and significance of each participant’s mean scores for each phase for decentering. The NAP analysis returned moderate effect sizes P1, P3 and P4, with a weak effect for P2 when data was considered individually; no results were statistically significant. However, when the data was combined the hypothesis that the treatment produced sustained increases in decentering was supported as there was statistically significant 75 WO 2025 / 160483                                   PCT / US2025 / 013057 increase in decentering from baseline to intervention phase, with a strong effect size. TABLE 4 Decentering scores: Phase Duration (days) Mean Score (SD) PPT A B A B NAP P Sig 1 13 37 17.5(8.4) 30.1 (12.7) 0.85 0.11 0.05 2 27 23 26.1 (3.1) 23.0 (8.2) 0.50 0.58 0.05 3 14 36 49.4(13.0) 70.5(11.4) 0.82 0.31 0.05 4 32 18 11.1 (12.8) 40.6(12.7) 0.92 0.22 0.05 Combined 86 114 23.0(10.2) 43.1 (11.5) 0.93 0.03* 0.05

[474] Secondary Hypotheses

[475] Visual analysis was conducted on secondary outcomes of craving, positive affect (PA), negative affect (NA), and awe. TABLE 5 shows means, RT and NAPS for combined data of each variable. TABLE 5 Secondary outcome measurements: Phase Duration (days) Mean Score (SD) PPT A B A B NAP P Sig Craving 86 114 59.7(12.1) 45.1 (20.1) .16 .15 0.05 PA 86 114 47.0(15.0) 38.9(17.6) .44 .21 0.05 NA 86 114 38.2 (25.4) 34.0 (29.6) .35 .44 0.05 Awe 86 114 32.5(16.5) 48.9(17.4) .75 .21 0.05

[476] The changes in mean from baseline to intervention are in the predicted direction for the secondary outcomes, except PA which unexpectedly decreased. However, no tests reached statistical significance, and all reported negligible effect sizes, except Awe, for which there was a moderate effect. FIGS. 14-17 display the plots for secondary outcomes. In FIGS. 14-17, the y-axis depicts craving, the x-axis depicts number of days, the solid line to the left of the vertical dashed line depicts the baseline trend, the solid line to the right of the vertical dashed line depicts the intervention trend, the vertical dashed line depicts the transition, and the horizontal dashed lines depict the median levels of the baseline and intervention trends.

[477] Discussion. The aim of this study was to quantitatively evaluate changes in self-reported measures of decentering and experience avoidance, whilst qualitatively assessing the therapeutic relevance of disclosed methods, particularly mystical-type experiences.

[478] The primary hypotheses were partially supported. That is, whilst statistical and visual analysis did not support the hypothesis that the treatment decreases experiential avoidance, the hypothesis that the treatment increases decentering was supported by the data. And whilst no single-case analysis for either primary outcome was statistically significant, the significant overall effect of the treatment on decentering displayed a large effect size. Regarding null findings for secondary hypotheses, in general, the results were in the predicted direction. One exception was positive affect, which decreased overall after the treatment was introduced. One explanation for this is that the early stages of abstinence are associated with positive affect due to a loss of coping response to stress (Witkiewitz et al. Alcohol Res. 2020 Sep 24;40(3):01). Another relates to the observation that each participant had ongoing stressors; there may also have been a drop in positive affect related to expectations or loss of anticipation. It was noted that some participants held high expectations for the treatment.

[479] With respect to therapeutic relevance, the case studies and participant experiences reported at followup converged to support the thesis that psychedelic experiences are therapeutic when delivered according to disclosed methods. For example, two of the four participants described their ketamine experiences as “lifechanging.” However, there was only limited evidence that participants experienced the characteristics of mystical-type experiences. Elements of mystical-type were reported, such as a sense of connectedness (P1, P2), and participant 3 described her experiences as “spiritual”. Saliently, two participants reported experiences akin to the concept of ego-death, sometimes viewed as a negatively-valenced form of ego-dissolution (Kolp et al. Int J Transpers Stud. 2014;33(2):84-140). Despite being distressed at the time, both participants reported insight and enhanced understanding of their problems after these experiences. Interestingly, there was only sparse reference to ketamine’s dissociative effects (P1 spoke of seeing herself ‘from a different angle’ and P2 described feeling like he left his body).

[480] More broadly, participants described nuanced and idiosyncratic accounts of their ketamine experiences, which included traveling around the cosmos (P1), galloping with horses and sailing in the ocean (P2), ‘creating beautiful worlds with golden flamingoes’ (P3), and navigating ‘dark, hellish’ environments in a cocoon (P4). Whilst these are consistent with ketamine’s psychedelic phenomenology (e.g., Kolp et al. Int J Transpers Stud. 2014;33(2):84-140), they are not so clearly indicative of mystical-type experiences. Themes of connection (P1) and self-acceptance (P3, P4) did emerge from acute experiences, and emotional openness post-ketamine was also consistent with qualitative research with ketamine (Breeksema et al. Psychopharmacol (Berl). 2023;240(7):1547-1560) and psilocybin (Watts etal. J Humanist Psychol. 2017;57(5):520-564).

[481] This study was not specifically designed to test the efficacy of the treatment, but 3 of the 4 participants reported successfully maintaining abstinence. Pi’s alcohol intake did not change, and even increased during treatment. P1 attributed this to stressful life events during the treatment and at follow-up reflected that the treatment may have been more successful if she aimed for abstinence rather than aiming to change her relationship to alcohol.

[482] Returning to the primary hypotheses, the null result for experiential avoidance offers many interpretations. Alcohol-related experience avoidance may not have been targeted by the treatment, may not be a relevant target in this subclinical sample, or may have been poorly operationalized in the current study. The latter interpretation is supported by the well-documented problems with measures relating to psychological WO 2025 / 160483                                   PCT / US2025 / 013057 flexibility which are often criticized for lacking validity and reliability (Doorley et al. Soc Personal Psychol Compass. 2020; 14(12): 1-11). Moreover, this single-item measure was created for the current study (but based on the wording of existing measures and designed to be relevant to the target behavior - urges to drink alcohol) and so was unvalidated.

[483] In contrast, the decentering measure was multi-item, unrelated to the target behavior, derived from a factor analytic model of metacognition, and previously evidenced to be sensitive to change at the state level and to mediate the relationship between mindfulness and reductions in clinical outcomes (Hanley et al. Psychol Assess. 2020;32(10):956-971). Therefore, it seems reasonable to conclude that, in contrast to experiential avoidance, decentering was successfully operationalized in the current study, and hence the findings highlight a specific mechanism of the treatment. However, it was notable that most of the self-report measures displayed trends at baseline, which calls into question the validity of the scales used, although this is perhaps unsurprising given that single-case experiments are designed to test causality in directly observable behavior (Kratochwill. Single-Case Research Design and Analysis: An Overview In: Single-Case Research Design and Analysis (Psychology Revivals). 1st ed. Routledge: 2015).

[484] With respect to the extant literature, experiential avoidance is a less established construct than decentering. Originally formulated by Beck as cognitive-distancing (Beck. Cognitive therapy and the emotional disorders. International Universities Press Inc.: 1975), decentering is only one of many conceptually overlapping constructs. In the clinical literature, several conceptually similar metacognitive processes have been proposed, including self-as-context, observer-state, metacognitive awareness, self-distanced perspective (Grieger. From a linear to a contextual model of the ABC's of RET. In A. Ellis & R. M. Grieger (Eds.), Handbook of rationalemotive therapy. Springer Publishing Company; 1985; Safran & Segal. Interpersonal process in cognitive therapy. Jason Aronson; 1990; Hayes et al. Acceptance and Commitment Therapy: An experiential approach to behavior change. Guilford Press; 1999), suggesting a primary role for enhanced awareness of or a decoupling from internal experiences in facilitating psychotherapy, including but not limited to mindfulness-based interventions. The extent to which increased decentering resulted from mindfulness components of the protocol, ketamine’s neuroplastic properties, or a combination of these and other factors (e.g., priming, expectancy effects) is not possible to infer from the current study design. The positive results reported for decentering are consistent with the metacognitive model of mindfulness (Jankowski & Holas. Conscious Cogn. 2014;28:64-80) and a recent review suggesting psychedelic states facilitate mindfulness (Radakovic et al. J Psychedelic Stud. 2022;6(2): 137-153).

[485] However, from the qualitative findings reported, there is supportive evidence that decentering is mechanistic. For example, at follow-up, P4 stated, “there's definitely a pattern after the ketamine, I'm very mindful... but after a few days it drops,” and P3 said the treatment made her “feel a lot more able to just observe without immediate reaction.” Interestingly, P3 did not report practicing mindfulness between sessions (whereas P4 did and had a history of mindfulness practice). Alternatively, however, priming and expectancy effects could WO 2025 / 160483                                   PCT / US2025 / 013057 explain these reflections.

[486] Overall, though, the qualitative findings were more supportive of the experience-oriented model of disclosed methods. From a therapeutic perspective, the emotional themes of the ketamine experience appeared most clinically relevant, whether they be realizations about the impact drinking had on a person’s past (P2, P3) or where continued drinking would lead to in the future (P1). These varied in valence, from intense fears from death-like experiences (P1) to profound and novel feelings of love and self-acceptance (P3), to deep feelings of sadness and empathy for significant and / or deceased loved ones (P2). Perhaps indicating a sensitization to ketamine, the participant (P4) with the most prior experience of taking ketamine reported the least efficacy. Whilst P4 maintained abstinence, she did not feel like the treatment addressed the underlying cause of her problematic drinking.

[487] Limits and Strengths. Single-case designs have weak external validity, limiting generalizability, but when well-designed, possess high internal validity, allowing inferences about causality to be made. Despite limitations, the single-case mixed design proved an effective method for assessing mechanisms of the treatment. A complex interplay of common and specific therapy factors, factors relating to set and setting, and various confounds will have influenced the outcomes and the participants' and researcher’s perspective on the treatment. Nonetheless, the mixed methods design allowed for a rich illustration of the psychological mechanisms at play.

[488] Clinical Implications. This study suggests that disclosed methods comprising administering esketamine, combined with Mindfulness-Based Relapse Prevention (MBRP), is synergistic, and specifically, through increasing decentering may support alcohol abstinence by allowing distance from thought processes that lead to relapse. The mixed methods approach allowed important feedback about the treatment to emerge. For example, Pi’s feedback suggests the potential utility of defining clear objectives related to alcohol consumption (e.g., abstinence vs. moderation) at the outset of therapy. Also, in general participants found both the MBRP and non-MBRP therapeutic content to be important, and all felt the psychotherapy component was necessary but varied in how they felt this should be organized (e.g., therapy time before vs. after ketamine). Relatedly, the case studies highlighted the importance of the ketamine sessions in aiding the therapeutic alliance and providing much more depth to the initial formulations (e.g., P1 identifying activation of a core belief from childhood). And the distress associated with certain experiences (like ego-death) highlights the importance of providing subjects with a safe and supportive environment during and after the ketamine administration.

[489] Conclusion. In conclusion, this mixed-methods design enabled the investigation of a disclosed method by measuring daily variation of alcohol-related experiential avoidance and decentering in response to the treatment at the level of the individual, while also providing insights into acute aspects of participants’ ketamine experience, with the strengths of one method offsetting the weaknesses of the other. Acknowledging any methodological shortcomings, it is noteworthy that the strongest combined effect sizes emerged for decentering and awe. The quantitative findings provide evidence that disclosed methods causally increase decentering, and WO 2025 / 160483                                   PCT / US2025 / 013057 perhaps the experience of awe. When these findings are considered alongside the case studies and follow-up interviews of participant experiences, the profundity stemming from ketamine’s diverse psychedelic phenomenology appears to be a primary therapeutic property. EXAMPLE 2. Esketamine with Mindfulness-Based Intervention for Problem (Hazardous) Drinkers

[490] A study was performed, involving an S-ketamine OTF plus manualized relapse prevention cognitive behavioral therapy (“CBT”) for AUD. The mechanistic study, comprising 28 people who were harmful drinkers, investigated the impact of a single dose of the S-ketamine OTF on dissociation and alcohol cravings. The S-ketamine OTF was well-tolerated by all participants, with no reports of serious adverse effects. The S-ketamine OTF exhibited significantly greater dissociative effects than placebo, which were of a magnitude observed with doses of intravenous racemic ketamine given in clinical treatment. Results are also published in Gent et al. J Psychopharmacol. 2024;38(6):541 -550, hereby fully incorporated by reference.

[491] The S-ketamine OTF demonstrated a statistically significant reduction in alcohol cravings in participants compared to the placebo.

[492] Participants and Design. Twenty-eight participants were recruited from the community using social media advertisement, all participants met the criteria for hazardous drinking on the Alcohol Use Disorder Identification Test (AUDIT) (a score > 8), were above the age of 18, were fluent English speakers, and were seeking to reduce their alcohol consumption. Individuals were excluded if they had a history of psychosis or schizophrenia, were in treatment for a substance use disorder (SUD), had high blood pressure (>140 / 90) upon screening, had a body mass index (BMI) less than 16 or greater than 35, were on any medication contraindicated for use with ketamine, or produced a positive urine screen for ketamine.

[493] This was a double-blind placebo-controlled mixed within- and between-measures study. Participants enrolled in a two-week-long study where they were randomized in a 1:1 ratio to receive either esketamine hydrochloride in the form of two oral thin film strips (total dose = 115.1 mg) or two strips of oral thin film vitamin C (placebo). Participants came into the study center twice during the study: 1) for a screening visit (day 1) and 2) for drug administration (day 8) and provided online follow-up data on day 14. The study was approved by the institutional committee and all participants gave written, informed consent.

[494] Procedure. Participants visited the study center for two sessions - an initial screening visit where their body mass index (BMI), blood pressure and urine was assessed to determine eligibility with baseline measures completed immediately afterwards. They were given a daily mindfulness practice to complete each day for the next week. Participants then returned seven days after the baseline visit for the drug administration visit. On this visit, participants completed several measures of psychological well being, mindfulness and alcohol craving (see FIG. 1) and were breathalyzed to ensure they were alcohol-free. They were given the oral thin film of esketamine or placebo, and once the drug had been administered, participants were given an eye mask to wear, and the option to listen to some soothing music through their headphones for 40 minutes. They then completed some post-drug follow up measures. They were again given a daily mindfulness practice for the next WO 2025 / 160483                                   PCT / US2025 / 013057 seven days. Follow up measures were completed online 14 days following the baseline visit.

[495] Mindfulness-based Intervention (MBI). During the screening visit, participants listened to three introductory mindfulness recordings, which described the benefits of mindfulness-based relapse prevention and helped provide the tools necessary to acknowledge alcohol cravings. For the duration of the study, participants were prompted to complete 14 daily MBI sessions via email, each lasting between 5-25 minutes.

[496] The mindfulness sessions provided participants with a basic meditation practice suitable for beginners, letting subjects become relaxed and centered, embracing any thoughts or sensations during the experience. On days seven and 14, subjects received an addiction and relapse prevention mindfulness practice. This session was tailored more specifically to problem drinking, helping participants recognize and acknowledge alcohol cravings while focusing on the ‘four ways’: breathing mindfully, recognizing body signals, acknowledging thoughts, and allowing the mind to wander.

[497] Drug Administration. During the 2nd week of the study, on day 8, participants came to the research center, and received either esketamine HCI in the form of two oral thin film strips (total dose = 115.1 mg; LTS Lohmann) or vitamin C (placebo, Bon Ayu) using a 1:1 ratio. Participants were required not to consume alcohol for 24 hours, to fast for four hours, and to only consume clear liquids two hours prior to the administration to reduce the risk of vomiting. Participants were prepared for the esketamine experience they may encounter via a script read by the researcher. Once dosed, subjects listened to relaxation music for 40 minutes.

[498] Measures. Engagement. Psychological and physical engagement in MBI, both measured using a five-point scale, from 1 (extremely likely) to 5 (extremely unlikely), was adapted from Banerjee etal. (2018).

[499] Mindfulness. Mindfulness was measured using the Five Facets of Mindfulness Questionnaire (FFMQ-15; Baer et al., 2012), a 15-item questionnaire assessing five subscales of mindfulness: observing, describing, acting with awareness, non-judgement, and non-reactivity. Additionally, the Mindfulness Attention Awareness Scale (MAAS; Brown and Ryan, 2003), a 15-item questionnaire, was also used to assess mindfulness.

[500] Alcohol-related outcomes. Alcohol-related secondary outcomes, such as craving and alcohol consumption, were assessed using the Alcohol Graving Questionnaire Short-Form Revised (ACQ-SF-R; Singleton, 1995) and the Timeline Follow-Back Method (TLFB; Sobell and Sobell, 1992), respectively.

[501] Subjective effects of esketamine. Dissociative states were measured using the Clinician-Administered Dissociative States Scale (CADSS; Bremner et al., 1998); subjective effects of esketamine, measured by the Bodily Symptoms Scale (BSS; Morgan et al., 2004); mystical experiences, measured by the Mystical Experience Questionnaire (MEQ-30; Pahnke, 1963).

[502] Mood and Wellbeing. Depressive symptoms were measured with the Eight-item Patient Health Questionnaire for Depression (PHQ-8; Kroenke et al., 2009); anxiety symptoms, by the Generalized Anxiety Disorder Assessment (GAD-7; Spitzer et al., 2006); and general wellbeing, measured by the WarwickEdinburgh Mental Well-being Scale (WEMWBS; Tennantetal., 2007).

[503] Statistical analysis. A detailed analysis plan was pre-registered at Open Science Framework, at the URL https: / / doi.org / 10.17605 / OSFJO / 5SY4C, all of which is incorporated by reference as if fully set forth herein.

[504] To analyze participant demographics between groups, independent sample t-tests were conducted, and chi-squared statistics were reported for categorical data. For continuous data, a Mann-Whitney U statistic was reported if the data was non-parametric. Main analyses of engagement, alcohol craving, and mindfulness changes were analyzed using multilevel modeling with time and group as the fixed effects variables and participants as the random effects variable was used to analyze. Secondary outcomes, such as mystical experiences, were analyzed using an independent t-test. Jamovi Version 2.3 was used to conduct all analyses.

[505] Mediation analysis was used to examine whether changes in engagement mediated changes in alcohol cravings. The jAMM model in Jamovi with bias-corrected 95% confidence intervals and the bootstrapping method with 5000 samples were used for the analyses.

[506] Results. Thirty-eight individuals were recruited, and after exclusions and drop-outs, twenty-eight participants were enrolled in the study. See TABLE 6 for participant demographic data. Both groups were similar in their demographic characteristics with no significant differences in any of the demographic variables following Mann Whitney U or chi-squared tests. TABLE 6 Participants’ characteristics of both esketamine and placebo conditions: Esketamine (N = 14) Placebo (N = 14) Test Statistic p value Age (Years) (M (SD)) 21.1 (1.4) 22.1 (3.7) U (26) = 78.50 .362 Gender M: F(N) 8:6 8:6 x2(1) = 0.00 1.000 Ethnicity Mixed:White:Other (N) 1:13:0 0:13:1 X2(2) = 2.00 .368 AUDIT Score (M (SD)) 15.3(5.8) 14.3(5.9) U (26) = 82.00 .474 Previous Mindfulness Experience Yes: No (N) 5:9 3:11 X2(1) = 0.70 .403 Previous Ketamine Use Yes: No (N) 10:4 6:8 X2(1) = 2.33 .127 Previous Cannabis Use Yes: No (N) 12:2 14:0 X2(1) = 2.15 .142 (N = number; M = mean; SD = standard deviation; x2 = Pearson’s Chi-squared; U = Mann Whitney U statistic.)

[507] Primary Outcome: Engagement (Psychological & Physical) in Mindfulness-Based Intervention

[508] In the mixed model analysis of psychological engagement, there was a significant main effect of group (F (1,26) = 6.88, p = .014) and time (F (2, 56) = 5.47, p = .007), as well as time-by-group interaction (F (2,52) = 6.45, p = .003). To further investigate these findings, a simple effects analysis revealed a significant difference between pre-drug and seven days post-drug for the esketamine condition (f (52) = -3.29, p = .002) but not for the placebo condition (f (52) = 1.71, p =.093). However, no significant main effect of time, group or time-by- WO 2025 / 160483                                   PCT / US2025 / 013057 group interaction was found for physical engagement.

[509] Mindfulness. For scores of mindfulness measured using the FFMQ-15, the mixed model analysis revealed no significant main effect of group or time and no significant time-by-group interaction, while using the MAAS, there was a significant main effect of time (F (1, 26) = 6.21, p =.019) where mindfulness increased over the study period but no main effect of group or interaction (displayed in TABLE 7). TABLE 7 Means and standard deviations for trait mindfulness (FFMQ-15 and MAAS scores): Esketamine Placebo Measure Timepoint M SD M SD FFMQ-15 Baseline 45.9 4.4 47.8 6.8 Pre-drug 45.5 3.5 46.9 4.4 Post-drug 1 45.1 4.8 47.5 4.5 Post-drug 2 48.1 7.7 46.4 4.4 7 days post-drug 45.9 3.7 45.3 4.8 MAAS Baseline 3.1 0.6 3.2 1.0 7 days post-drug 3.4 0.9 3.4 0.9 (where M = means; SD = standard deviation; FFMQ-15 = Five Facts of Mindfulness Questionnaire; MAAS = Mindfulness Attention Awareness Scale; Post drug 1 = 40 minutes post-drug; Post-drug 2 = following additional...

Claims

The invention claimed is:

1. A method of treating a substance use disorder (SUD) in a subject in need thereof, comprising:a. administering, during a drug-administration session, one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof;b. wherein the one or more pharmaceutical compositions are formulated as an oral transmucosal dosage form, suitable for buccal or sublingual administration;c. wherein the oral bioavailability of the esketamine is at least 25%; andd. wherein the one or more pharmaceutical compositions provide a dose of esketamine sufficient to produce dissociative effects, or a mystical experience, in the subject.

2. The method of claim 1, wherein the oral transmucosal dosage form is any of a tablet, a film, a lozenge, agum, a spray, a gel, a cream, an ointment, a powder, a granule, a patch, a strip, a sachet, a pouch, anoral solution, and a suspension.

3. The method of claim 2, wherein the film is an oral thin film (OTF).

4. The method of claim 1, wherein the SUD is any of alcohol use disorder (AUD); opioid use disorder (OUD);nicotine dependence or tobacco use disorder; sedative, hypnotic, and anxiolytic use disorder; stimulant use disorder; cannabis use disorder; hallucinogen use disorder; inhalant use disorder; and other substance use disorder.

5. The method of claim 4, wherein the SUD is alcohol use disorder (AUD).

6. The method of claim 5, wherein the AUD is harmful use AUD, dependent use AUD, alcohol abuse, alcohol dependence, or alcoholism.

7. The method of claim 5, wherein the AUD is classified as mild, moderate, or severe according to DSM-5.

8. The method of claim 4, wherein the SUD is opioid use disorder (OUD).

9. The method of claim 1, wherein the esketamine is administered in a dose of between about 100 mg andabout 200 mg, between about 100 mg and about 125 mg, between about 125 mg and about 150 mg, between about 150 mg and about 175 mg, or between about 175 mg and about 200 mg.

10. The method of claim 9, wherein the dose of esketamine is between about 110 mg and about 120 mg, or between about 170 mg and about 180 mg.

11. The method of claim 10, wherein the dose of esketamine is about 115.3 mg.

12. The method of claim 10, wherein the dose of esketamine is about 172.95 mg.WO 2025 / 160483                                   PCT / US2025 / 01305713. The method of claim 3, wherein the one or more pharmaceutical compositions are two OTFs each comprising 57.65 mg of esketamine, for a total dose of esketamine of 115.3 mg.

14. The method of claim 3, wherein the one or more pharmaceutical compositions are three OTFs each comprising 57.65 mg of esketamine, for a total dose of esketamine of 172.95 mg.

15. The method of claim 1, wherein producing dissociative effects or producing a mystical experience in the subject is determined using a psychometric rating scale.

16. The method of claim 15, wherein the psychometric rating scale is any one or more of the Hallucinogen Rating Scale (HRS), the Mystical Experience Questionnaire (MEQ), and the Addiction Research Center Inventory (ARCI).

17. The method of claim 1, wherein the method is effective to: (a) reduce use of a substance, (b) reduce cravings for a substance, (c) promote abstinence from a substance, (d) prevent relapse into use of a substance, (e) improve a symptom of the SUD, (f) reduce the severity of a diagnostic criterion of the SUD, (g) improve a score on an assessment, or (h) improve a score or result on an outcome measure.

18. The method of claim 17, wherein the assessment is any of the Severity of Alcohol Dependence Questionnaire (SADQ), the Mini International Neuropsychiatric Interview 5 (MINI 5), the Columbia Suicide Severity Rating Scale (C-SSRS), the Alcohol Dependence Syndrome section of the SCID-5-CT (Clinical Trials Version), the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7 (GAD-7), the Short Inventory of Problems for Alcohol (SIP), the Alcohol Timeline Follow Back (TLFB), the Clinical Institute Withdrawal Assessment for Alcohol—Revised Version (ClWA—Ar), the Penn Alcohol Craving Scale (PACS), the Obsessive Compulsive Drinking Scale (OCDS), the Pittsburgh Sleep Quality Index (PSQI), the Interpersonal reactivity Index (IRI), the Short Form (36) Health Survey (SF-36), the SelfCompassion Scale (SCS), and the Trauma History Questionnaire (THQ).

19. The method of claim 17, wherein the outcome measure is any of increased decentering, increased awe, increased positive affect, decreased negative affect, decreased experiential avoidance, increased frequency of mystical-type experiences, reduction of substance use, reduction of substance cravings, a promotion of substance use abstinence, a prevention of relapse into substance use, an improvement of at least one symptom of substance use disorder, an increase in quality of life, an increase in psychosocial functioning, a decrease in use or frequency of a prescription medication, a decrease in use or frequency of a recreational drug, a decrease in obsessive compulsive thoughts, a decrease in suicidality, an increase in feelings of empathy, an increase in self-compassion, a reduction in the frequency of substance use, a reduction in drive or urge to engage in substance use, prolonged abstinence from substance use, reduction in severity of symptoms of substance use, and reduction in the time spent on substance use.WO 2025 / 160483                                   PCT / US2025 / 01305720. The method of claim 1, further comprising adjunctive psychotherapy.

21. The method of claim 20, wherein the adjunctive psychotherapy is a psychosocial or behavioral therapy.

22. The method of claim 21, wherein the psychosocial or behavioral therapy is a ketamine-assisted psychotherapy (KAP), a mindfulness-based intervention, a standardized psychological treatment, motivational interviewing, Internal Family Systems (IFS) therapy, or any combination thereof.

23. The method of claim 22, wherein the mindfulness-based intervention is Mindfulness-Based Relapse Prevention (MBRP), Mindfulness-Based Stress Reduction (MBSR), Mindfulness-Based Cognitive Therapy (MBCT), Dialectical Behavior Therapy (DBT), Acceptance and Commitment Therapy (ACT), Mindfulness Interviewing, and Cognitive Behavioral Therapy (CBT), or any combination thereof.

24. The method of claim 22, wherein the KAP is KAP based on the protocols of Ketamine for reduction of Alcohol Relapse (KARE) or KAP based on the KARE Therapy Programme Guidebook.

25. The method of claim 1, wherein the subject has a comorbid mental health disorder, a comorbid behavioraladdiction, or a comorbid neurodegenerative disorder.

26. The method of claim 25, wherein the comorbid mental health disorder is any of post-traumatic stress disorder (PTSD), an adjustment disorder, an affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, a phobia disorder, a binge disorder, body dysmorphic disorder, a mood disorder related to another health condition, a disruptive behavior disorder, an eating disorder, an impulse control disorder, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), a personality disorder, an attachment disorder, or a dissociative disorder.

27. The method of claim 25, wherein the comorbid behavioral addiction is any of gambling disorder, compulsive sexual behavior disorder, compulsive buying-shopping disorder, internet addiction, gaming disorder and internet gaming disorder, risk-taking addictions, kleptomania, pyromania, pornography addiction, technology addiction, binge eating disorder, “workaholism,” perfectionism, pathological skin picking, exercise addiction, tanning addiction, tattoo addiction, masturbation addiction, sex addiction, and love addiction.

28. The method of claim 25, wherein the comorbid neurodegenerative disorder is any of Alzheimer’s disease, amyotrophic lateral sclerosis, Charcot’s disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder,WO 2025 / 160483                                   PCT / US2025 / 013057Parkinson’s disease, Parkinsonisms, prion disease, progressive supranuclear palsy, and traumatic brain injury (TBI), including mild traumatic brain injury (mTBI).

29. The method of claim 25, wherein administering one or more pharmaceutical compositions comprising esketamine according to said method also treats the comorbid mental health disorder, the comorbid behavioral addiction, or the comorbid neurodegenerative disorder.

30. The method of claim 1, further comprising a second drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject.

31. The method of claim 30, further comprising a third drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject.

32. The method of claim 31, further comprising a fourth drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject.

33. The method of claim 32, further comprising a fifth drug-administration session, wherein one or more pharmaceutical compositions comprising esketamine, or a pharmaceutically acceptable salt thereof, are administered to the subject.

34. The method of claim 1, further comprising providing the subject with one or more sessions of adjunctive psychotherapy separate from the drug-administration session.

35. The method of claim 1, further comprising administering to the subject an additional active agent.

36. The method of claim 35, wherein the additional active agent is any of an amino acid, an antioxidant, ananti-inflammatory agent, an analgesic, an antineuropathic or antinociceptive agent, an antimigraine agent, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, a cannabinoid, a dissociative, an immunostimulant, an anti-cancer agent, an antiemetic, a hormone, an orexigenic, an antiulcer agent, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotectant, an entactogen or empathogen, an entheogen, a psychedelic, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenethylamine, a sedative, a serotonergic agent, a hypnotic, an analeptic, a psychoneurotropic, a neuro-muscle blocker, an antispasmodic, an antiallergic, a cardiotonic, an antiarrhythmic, a diuretic, a hypotensive, a vasopressor, an antitussive, an antidiabetic, an antitumor agent, a chemotherapeutic, a narcotic, a stimulant, a vitamin, a SSRI, a SNRI, a NRI, a NDRI, a TCA, a benzodiazepine, an opioid antagonist, a CB1 antagonist, a CRH1 receptor antagonist, a NK1R antagonist, an OTR agonist, a GABA agent, a voltage-gated sodium channel inhibitor,a voltage-dependent calcium channel agonist, an a7 nicotinic acetylcholine receptor agonist, a 5-HT3 antagonist, a 5-HT1A receptor partial agonist, a 5-HT2A receptor antagonist, a 5-HT reuptake inhibitor, a SERT inhibitor, an a1 adrenoreceptor antagonist, a glucocorticoid receptor antagonist, an a1 adrenoreceptor agonist, an AChE inhibitor, a dopamine D2 receptor antagonist, an a2 adrenoreceptor agonist, a NMDA modulator, an aldehyde dehydrogenase inhibitor (e.g., disulfiram), a phenylethylamine, and a serotonergic agent, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising esketamine formulated as an oral transmucosal dosage form, for use in the method of any claims 1-36.

38. The pharmaceutical composition of claim 37, wherein the oral transmucosal dosage form is an oral thin film (OTF).

39. Use of a pharmaceutical composition comprising esketamine, formulated as an oral transmucosal dosage form, in the treatment of an SUD according to the method of any claims 1-36.

40. Use of the pharmaceutical composition of claim 39, wherein the SUD is AUD or OUD.

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