Methods of treating psychiatric disorders or pain using (r)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one or pharmaceutically acceptable salts thereof

Abstract

The present disclosure relates to methods of treating a patient having a psychiatric disorder or pain comprising administering to the patient in need thereof a base compound or a pharmaceutically acceptable salt thereof as defined herein in specific dosing regimens.

Description

In other embodiments, the psychiatric disorder is a bipolar or related disorder. Some examples of bipolar and related disorders include bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorder, and bipolar and related disorder due to another medical condition. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a bipolar or related disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a substance-related, disorder. Substance use disorders typically involve abuse of psychoactive compounds, such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine and tobacco, cocaine, amphetamine / methamphetamine. As used herein "substance" or "substances" are psychoactive compounds that can be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine and tobacco. The method described herein may be used for treating or preventing a substance use craving, diminishing a substance use craving, and / or facilitating substance use cessation or withdrawal. In some embodiments, the method may be used to facilitate smoking cessation or cessation of opioid use. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a substance-related disorder, including any of those specifically pointed out above by any of the method s described herein. In other embodiments, the psychiatric disorder is an anxiety disorder. Some examples of anxiety disorders include separation anxiety disorder, selective mutism, mood disorder, specific phobias, such as, but not limited to, acrophobia, aerophobia, aquaphobia, astraphobia, agoraphobia, claustrophobia, enochlophobia, hemophobia, zoophobia, glossophobia, iatrophobia, dentophobia, mysophobia (germophobia), and the like, social anxiety disorder (social phobia), panic disorder, panic attack, generalized anxiety disorder, substance / medi cation-induced anxiety disorder, and anxiety disorder due to another medical condition. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat an anxiety disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is an obsessive-compulsive or related disorder, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, substance / medication-induced obsessive-compulsive and related disorder, and obsessivecompulsive and related disorder due to another medical condition. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat an obsessive-compulsive or related disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a trauma- or stressor-related disorders. Some examples of such psychiatric disorders include reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder, acute stress disorder, and adjustment disorders. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a trauma- or stressor-related disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a feeding and eating disorder. Some examples of such psychiatric disorders include anorexia nervosa, bulimia nervosa, binge-eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a feeding or eating disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a neurocognitive disorder. Some examples of neurocognitive disorders include delirium, major neurocognitive disorder, mild neurocognitive disorder, major or mild neurocognitive disorder due to Alzheimer’s disease, major or mikl frontotemporal neurocognitive disorder, major or mild neurocognitive disorder with Lewy bodies, major or mild vascular neurocognitive disorder, major or mild neurocognitive disorder due to traumatic brain injury', substance / medication-induced major or mild neurocognitive disorder, major or mild neurocognitive disorder due to HIV infection, major or mild neurocognitive disorder due to prion disease, major or mild neurocognitive disorder due to Parkinson’s disease, major or mild neurocognitive disorder due to Huntington’s disease, major or mild neurocognitive disorder due to another medical condition, and major or mild neurocognitive disorder due to multiple etiologies. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a. neuroc-ognitive disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a neurodevel opmen tai disorder. Some examples of neurodevel opmental disorders include autism spectrum disorder, attention-deficit / hyperactivity disorder, stereotypic movement disorder, tic disorders, Tourette’s disorder, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a neurodevelopmental disorder, including any of those specifically pointed out above by any of the methods described herein. In some embodiments, a variety of other psychiatric or neurological conditions may be treated according to the methods of the present disclosure. In some embodiments, such psychiatric and neurological conditions include, but are not limited to, a. learning disorder, autistic disorder (e.g., autism spectrum disorder), attention-deficit hyperactivity disorder, Tourette's syndrome, phobia, post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer's disease, Parkinson's disease, spasticity, myoclonus, muscle spasm, bipolar disorder, a substance abuse disorder, urinary incontinence, and schizophrenia. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat these other psychiatric and neurological disorders, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is a personality disorder. The personality disorder may be within any of the known clusters, e.g., clusters A, B, or C. Some examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, histrionic personality disorder, avoidant personality disorder, obsessive-compulsive personality disorder, and dependent personality disorder. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a personality disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder may be associated with a sexual dysfunction. Some examples of such psychiatric disorders include delayed ejaculation, erectile disorder, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / penetration disorder, male hypoactive sexual desire disorder, premature (early) ejaculation, and substance / medication-induced sexual dysfunction. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat a sexual dysfunction disorder, including any of those specifically pointed out above by any of the methods described herein. In other embodiments, the psychiatric disorder is gender dysphoria. The base compound or a pharmaceutically acceptable salt thereof described in this disclosure may be administered to treat the gender dysphoria by any of the methods described herein. In another aspect, the present disclosure is directed to treating pain afflicting the subject. Such pain syndromes may include, but are not limited to, chronic pain, neuropathic pain, chemotherapy induced neuropathy, or pain associated with headache disorders such as a migraine, cluster headache, or other headache disorders. In the method, the base compound or a pharmaceutically acceptable salt thereof described herein, typically in the form of a pharmaceutical composition, is used to treat the pain using any one of the methods described herein. These methods described herein provide an improvement (typically, a lessening of or a shortening of the duration of) in the pain symptoms. In an embodiment, the treatment with the base compound reduces the intake of opioid agonist analgesics (e.g., a decrease in the dose and / or frequency of their administration) that the patient is alternatively using to control their pain. Pursuant to the present disclosure, there are two phases of treatment for treating psychiatric disorders. The first phase of treatment is the acute induction period of treatment. It commences from the first administration of the base compound or a pharmaceutically acceptable salt thereof to a subject suffering from a psychiatric disorder and concludes when neuropsychiatric symptoms are in remission. .At the conclusion of the acute induction period, qualitative neuropsychiatric symptoms indicative of depression, such as persistently sad mood, decreased interest in usually pleasurable activities, reduced appetite and weight loss or increased appetite and weight gain, feelings of hopelessness, fatigue, decreased or increased sleep, poor concentration and suicidal ideation / behavior, and the like are in remission and do not manifest itself. This can be observed by a medical professional, such as a doctor, or a nurse or medical technician in the psychiatric field. Remission of the neuropsychiatric symptoms can also be measured by a series of screening characteristics or symptoms exhibited by the subject, as evaluated by a health care professional and rating the characteristics or symptoms on a graduated scale, assigning points to various symptoms that would be manifested in a subject suffering from a mood disorder, with the less intense characteristics and / or symptoms assigned a lower value and the more intense characteristics or symptoms assigned a higher value, with the final score being the addition of the point value of each of the characteristics or symptoms assigned by the health care professional. For example, one such test is the Hamilton Depression Rating Scale, which asks the clinician to rate the subject based on an interview with the subject regarding the following symptoms: 1) depressed mood, 2) feelings of guilt, 3) suicidal thought or action, 4) insomnia initial, 5) insomnia middle, 6) insomnia late, 7) work and interests (assessing pleasure and functioning), 8) motor retardation, 9) motor agitation, 10) psychic anxiety, 11) somatic anxiety, 12) gastrointestinal somatic symptoms, 13) general somatic symptoms, 14) genital symptoms, 15) hypochondriasis, 16) weight loss, and 17) insight. A score of less than or equal to 7 on this scale is indicative of the remission of the neuropsychiatric symptoms. Another test is Montgomery-Asberg Depression Rating Scale, in which the clinician rates the subject on the following symptoms exhibited by a subject in a clinical interview: 1) apparent sadness; 2) reported sadness, 3) inner tension; 4) reduced sleep, 5) reduced appetite, 6) difficulty in concentration; 7) lassitude; 8) inability to feel (assessing pleasure and functioning); 9) pessimistic thoughts; 10) suicidal thoughts. The test is usually conducted by a health-care professional, in which the subject is asked questions in the categories enumerated above, and the answers are rated on a scale. A score of less than or equal to 10 on this scale is indicative of the remission of the neuropsychiatric symptoms. This acute induction phase in an embodiment lasts usually for a period of less than 6 months after the first dose of the base compound or a pharmaceutically acceptable salt thereof is administered to the subject suffering from a psychiatric disorder, and in another embodiment, up to about four months after the first dose of the base compound or a pharmaceutically acceptable salt thereof is administered to the subject suffering from a psychiatric disorder. In an embodiment, it lasts from about 4 to about 16 weeks, in another embodiment from about 4 to about 8 weeks and in another embodiment, from about 4 to about 6 weeks after administration of the first dose of the base compound or a pharmaceutically acceptable salt thereof to the subject suffering from a psychiatric disorder, provided there is adherence to the schedule described herein. However, there is no specific set time-period, as the length of this phase is dependent upon the progress of the subject, so in some cases, it may be shorter than the times described herein, and in other cases, it may be longer than the times described herein. At the conclusion of the acute induction phase of treatment, the second phase of treatment may commence, identified herein as the maintenance treatment phase, in which the subject being treated for a psychiatric disorder is periodically screened to determine if the clinical symptoms, i.e., neuropsvchiatric symptoms, remain in remission or sufficiently improved, and these symptoms are screened for a sufficient period of time to determine if the neuropsvchiatric symptoms remain in remission. The length of the maintenance treatment phase is determined by the psychiatrist or other medical professional that is treating the subject. In an embodiment, it lasts for about 8 weeks to about 52 weeks, and in another embodiment, from about 8 weeks to about 26 weeks from the commencement of the maintenance treatment phase, but it can be longer or shorter, dependent upon the subject’s condition, as determined by a medical professional, such as a psychiatrist. Towards the end of the maintenance treatment phase, the medical professional, such as a psychiatrist, will evaluate the subject one more time to ensure that the psychiatric disorder suffered by the patient remains in remission or otherwise sufficiently improved. Once the medical professional, such as the psychiatrist, determines that the psychiatric disorder is in remission for a sufficient time, the subject no longer is administered the base compound or a pharmaceutically acceptable salt thereof, and the maintenance treatment phase is concluded. If, however, the medical professional observes a worsening of the condition during the maintenance phase of treatment, the dosage or frequency of dosing of the base compound or a pharmaceutically acceptable salt thereof may be increased, as determined by the medical professional. Although the base compound or a pharmaceuti cally acceptable salt thereof may be administered by any means of administration, the amount administered may be described in terms of the concentration of base compound achieved in the plasma of the subject. In an embodiment, blood is drawn from the subject, and plasma is obtained from the blood by techniques known in the art. For example, plasma is obtained from blood that has been mixed with an anticoagulant in the collection tube and has, therefore, not clotted. This mixed blood may then be centrifuged, yielding plasma. The concentration of base compound in the plasma thus obtained is then measured by techniques known to one of ordinary skill in the art, for example, liquid chromatography-tandem mass spectrometry' (LC-MS / MS), and the like. The dosing regimen describes a method of treating a psychiatric disorder. In the acute induction phase of treatment, the dosing regimen described herein is therapeutically effective to treat a subject suffering from a psychiatric disorder to put into remission or substantially improve the neuropsychiatric symptoms associated with the psychiatric disorder. The dosing regimen described herein is therapeutically effective to maintain the neuropsychiatric symptoms associated with the psychiatric disorder in remission or substantially improved and minimize the risk of the subject having a relapse of the psychiatric disorder. However, due to typical intersubject variability in psychiatric disorders, it is to be understood that not all subjects will adequately respond to treatment with base compound. With respect to treating pain, the dosing regimen is one that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application as web as the frequency of the dose and the duration of the treatment wall vary from patient to patient, but also with the route of administration, the nature of the condition being treated, the age and general health of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage regimen ultimately being at the discretion of the attendant physician, in an embodiment, there are also tw'o phases of treatment, the acute induction phase of treatment, and the maintenance phase of treatment. Although the lengths of time and the dosing regimen administered to the patient of the two phases of treatment with respect to treating pain may overlap with the lengths of time and the dosing regimens for treating psychiatric disorder, the outward manifestation signs for the commencement and termination of each phase may be different. With respect to treating pain symptoms, the first dosage in the acute induction phase of treatment commences when the patient is treated for pain, i.e., 'when the medical personnel, such as a physician treating the pain administers the first dose of the base compound or pharmaceutically acceptable salts to the patient. The dosing schedule in the acute induction phase for treating pain is the same with respect to treating psychiatric disorders, but the patient suffering from pain symptoms may not need to be screened, as described hereinabove, as the patient who suffers from the psychiatric disorder. The acute induction phase of treatment when treating pain terminates when the patient no longer feels pain (“hereinafter referred to as the pain being in remission’"). At this point, the maintenance phase of treatment commences. Tn this embodiment, the maintenance phase of treatment has the same dosing regimen as the maintenance phase for the treatment of psychiatric disorders. However, the maintenance phase of treatment for treating pain, in this embodiment, terminates when the physician concludes that the pain has not returned for a sufficient time and that it is unlikely that the pain symptoms suffered by the patient will return. At this point, the physician will dismiss the patient. Unless the pain originally suffered by the patients reoccurs, the patient may not need any further treatment. If, again, the pain returns to the patient, then the physician will again treat the patient. In an embodiment, the present disclosure relates to a method of treating a psychiatric disorder and / or pain in a subject in need thereof comprising administering to said subject a base compound or a pharmaceutically acceptable salt thereof in one or more doses during an acute induction phase in an amount sufficient to achieve in said subject from each administration of the base compound or a pharmaceutically acceptable salt thereof after each dose an AUG ranging from about 390 to about 3,600 h ng / mL, wherein the base compound is substantially pure (R)-2-(4-fluorophenyl)~2-(methylamino)cyclohexan-l~one The frequency of the dosage is determined by one of ordinary' skill in the art , such as the psychiatrist or other doctor in the psychiatry field. In an embodiment, the acute induction phase concludes with the commencement of a. maintenance treatment phase that commences immediately after the conclusion of the acute induction period when neuropsychiatric symptoms from the psychiatric disorder are in remission or when the patient no longer suffers from the pain. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject at treatment interval ranging from every other week to three days a week for a period of about four to about six weeks during the acute induction period. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUG ranging from about 390 to about 2,100 h ng / mL during the acute induction period. In a further embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an AUC ranging from about 550 to about 1,800 h-ng / mL during the acute induction period. In an embodiment, the AUC is measured after the administration of a dose of the base compound or a pharmaceutically acceptable salt thereof, such as from about 0 to about 24 hours after its administration. In an embodiment, these values of the AUC and of the Cmax are for an approximately 65 to approximately 80 kg person, e g., about 70 kg person. At the conclusion of the acute induction phase, the maintenance treatment phase commences, wherein the objective is to maintain the remission or improvement of the neuropsychiatric and / or pain symptoms. The base compound or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve in said subject from each administration of the base compound or a pharmaceutically acceptable salt thereof after each dose an AUC ranging from about 390 to about 2,100 h-ng / mL. The frequency of the dosage is determined by one of ordinary skill in the art, such as the psychiatrist or other doctor in the psychiatry field. For example, to achieve this level, the base compound or a pharmaceutically acceptable salt thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to every other week basis for a period of at least 8 weeks or until the conclusion of the maintenance treatment phase. In an embodiment, the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h-ng / mL to about 1,800 h-ng / mL on a weekly to every other week basis. In another embodiment, the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase in an amount sufficient to achieve in the plasma of the subject an ALIC ranging from about 230 h-ng / mL to about 970 h-ng / mL on a weekly to daily basis to a subject in need thereof for a period of at least eight weeks during the maintenance treatment. In another embodiment, the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h ng / mL to about 760 h-ng / mL on a weekly to daily basis to a subject in need thereof during a maintenance treatment phase. In an embodiment, these values of the AUC are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. In another embodiment, the present disclosure relates to a method of treating a psychiatric disorder and / or pain in a subject in need of such treatment comprising administering the base compound or a pharmaceutically acceptable salt thereof to the subject in need of treatment during the acute induction phase in an amount sufficient to achieve a Umax in plasma ranging from about 72 ng / mL to about 540 ng / mL at treatment intervals ranging from every other week to three days a week. The dosage and the frequency of the dosage is determined by one of ordinary skill in the art, such as the psychiatrist or other doctor in the psychiatry field. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a Cmax in the plasma of the subject ranging from about 72 ng / mL to about 330 ng / mL during the acute induction period. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a Cmax in the plasma of the subject ranging from about 110 ng / mL to about 280 ng / mL during the acute induction period. Typically, the Cmax is measured after the administration of a dose of the base compound or a pharmaceutically acceptable salt thereof, such as from about 1 to about 3 hours after its administration for an oral dose, or immediately after injection for an IV bolus, or immediately on conclusion of the infusion for an IV infusion, or about 15 to about 30 minutes after administration for an IM injection. In an embodiment, these values of the Cmax are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. At the conclusion of the acute induction phase, the maintenance treatment phase commences, wherein the objective is to maintain the remission or improvement of the neuropsychiatric and / or pain symptoms. The base compound or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve in said subject after each dose a Cmax ranging from about 72 ng / mL to about 330 ng / mL. The frequency of the dosage is determined by one of ordinary skill in the art, such as the psychiatrist or other doctor in the psychiatry’ field. To achieve this level, in an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to every other week basis for a period of at least 8 weeks, or in an embodiment up to 52 weeks, or until the conclusion of the maintenance treatment phase. In an embodiment, the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase in an amount sufficient to achieve in the plasma, of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL on a weekly to every other week basis. In another embodiment, the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase is in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / tnL on a weekly to daily basis to a subject in need thereof for a period of at least eight w'eeks during the maintenance treatment. In another embodiment, the dose level of base compound or a. pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase is in an amount sufficient to achieve in the plasma of the subject a CmaK ranging from about 72 ng / mL to about 130 ng / mL on a weekly to daily basis to a subject in need thereof during a maintenance treatment phase. In an embodiment, these values ofCmax are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. For each of the Cmax values given hereinabove, the Cmax is measured about 1 to about 3 hours after administration of the base compound or a pharmaceutically acceptable salt thereof for an oral dose, or immediately after injection for an IV bolus, or immediately on conclusion of the infusion for an IV infusion, or about 15 to about 30 minutes after administration for an IM injection. In another embodiment, the present disclosure relates to a method of treating a patient afflicted with a. psychiatric disorder and / or pain comprising administering orally to a patient in need thereof the base compound or a pharmaceutically acceptable salt thereof during an acute induction phase of treatment at a dosage ranging from about 40 rag to about 360 mg relative to the base compound at treatment intervals ranging from every' other week to three days a week. The frequency of the dosage is determined by one of ordinary skill in the art, such as the psychiatrist or other doctor in the psychiatry field. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered orally at a dosage range of about 40 to about 180 mg relative to the base compound during the acute induction phase of treatment. In a further embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered orally at a dosage range of about 60 to about 140 mg relative to the base compound during the acute induction phase of treatment, and in a further embodiment, from about 140 mg to about 220 rag. In an embodiment, these dosage amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. At the conclusion of the acute induction phase, the maintenance treatment phase commences, wherein the objective is to maintain the remission or improvement of the neuropsychiatric and / or pain symptoms. The base compound or a pharmaceutically acceptable salt thereof is administered to the subject orally in an amount ranging from about 40 to about 180 mg and in another embodiment, from about 140 mg to about 220 mg, all of these dosage amounts being relative to the base compound on a twice weekly to every other week basis to the patient in need thereof for a period of at least 8 weeks, and in an embodiment up to 52 w'eeks, during a maintenance treatment phase that commences immediately after the conclusion of the acute induction period. The frequency of the dosage is determined by one of ordinary skill in the art, such as the psychiatrist or other doctor in the psychiatry field. In an embodiment the dose level of the base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about from about 40 to about 360 mg and in another embodiment, from about 40 to about 140 mg, and in a further embodiment, from about 140 mg to about 220 mg, with all of these dosage amount being relative to the base compound on a twice weekly to every other week basis. In a further embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject suffering from a psychiatric disorder ranging from about. 20 to about 100 mg relative to the base compound on a weekly to daily basis during the maintenance phase. In a further embodiment, the dose level of the base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about 40 to about 80 mg relative to the base compound on a weekly to daily basis during the maintenance treatment phase. In an embodiment, if administered orally, the base compound or a pharmaceutically acceptable salt thereof is administered as a single unit dose. In an embodiment, these amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject orally in an amount ranging from about 120 to about 240 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 150 ng / mL, io about 450 ng / mL. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject orally at a dose of 140 mg or 210 mg relative to the base1 compound. In another embodiment, the base compound is dosed daily, every other day, three days per week, twice per week, weekly, every other week, or monthly. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof during the acute induction phase or during the maintenance treatment phase or both phases for a psychiatric disorder or pain is administered concurrently with an antidepressant. The antidepressant may be administered simultaneously with or concurrently with the base compound or a pharmaceutically acceptable salt thereof, as defined hereinabove. In addition, the base compound or a pharmaceutically acceptable salt thereof may be administered by one route and the antidepressant may be administered by the same or different route to the subject. For example, the base compound or a pharmaceutically acceptable salt thereof may be administered orally and the antidepressant may also be administered orally or may be administered by a different route, such as by, for example, intravenously, or by inhalation or intramuscularly. In addition, in an embodiment, the antidepressant and the base compound or a pharmaceutically acceptable salt thereof may be mixed together prior to the administration to the subject. In an embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof blocks the serotonin transporter. In another embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is a selective serotonin reuptake inhibitor. In an embodiment, the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine. In a further embodiment, the antidepressant drug to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is a seroionin-norepinephrine reuptake inhibitor. In an embodiment, the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran. In another embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is a tricyclic or tetracyclic antidepressant. In a further embodiment, the tricyclic or tetracyclic antidepressant is imipramine, desipramine, amitriptyline, nortriptyline, amoxapine, clomipramine, dibenzepin, dosulepin, doxepin, lofepramine, maprotiline, norclomipramine, opipramol, protriptyline, trimipramine, mitrazapine, mianserin, or setiptiline. In another embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is bupropion. In another embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is a monoamine oxidase inhibitor (MAOI). In a further embodiment, the MAOI is isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, pirlindole, rasagiline, selegiline, or safinamide. In another embodiment, the antidepressant to be used simultaneously or concurrently with the base compound or a pharmaceutically acceptable salt thereof is gepirone. Ln additional embodiments, treatment with the base compound or a pharmaceutically acceptable salt thereof, for example, as a maintenance treatment phase, commences after an acute induction treatment with esketamine, arketamine, or racemic ketamine or combination thereof. As indicated hereinabove, the antidepressant may be administered by a different mode than the base compound or a pharmaceutically acceptable salt thereof. For example, the base compound or a pharmaceutically acceptable salt thereof may be administered orally, while esketamine, arketamine, or racemic ketamine is administered intravenously, intranasally, intramuscularly, subcutaneously, sublingually, or orally during the acute induction phase of treatment. For example, in an embodiment, esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously. In an embodiment, the present disclosure relates to a method of treating a patient having a psychiatric disorder or pain comprising administering the base compound or a pharmaceutically acceptable salt thereof concurrently with a selective serotonin reuptake inhibitor or a serotoninnorepinephrine reuptake inhibitor to a patient in need thereof on a daily basis, wherein the base compound or a pharmaceutically acceptable salt thereof is administered at a dosage level ranging from about 20 mg to about 100 mg relative to the base compound per day or in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 230 to about 970 hng / mL or a Cmax ranging from about 39 ng / mL to about 150 ng / mL. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered orally. In another embodiment, the daily dose of the base compound or a pharmaceutically acceptable salt thereof is administered as a single unit dose. In another embodiment, the daily dose of the selective1 serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is administered as a single unit dose. In a further embodiment, the daily dose of the base compound or a pharmaceutically acceptable salt thereof and the daily dose of the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor are administered together as a single unit dose in a single pharmaceutical composition. In an embodiment, the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, vortioxetine, duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran. In an embodiment, fluoxetine is administered at a daily dose ranging from about 10 to about 80 mg, paroxetine is administered at a daily dose ranging from about 10 to about 60 mg, citalopram is administered at a daily dose ranging from about 10 to about. 40 mg, escitaiopram is administered at a daily dose ranging from about 5 to about 20 mg, fluvoxamine is administered at a daily dose ranging from about 25 to about 300 mg, sertraline is administered at a. daily dose ranging from about 50 to about 200 mg, vortioxetine is administered at a daily dose ranging from about 5 to about 20 mg, duloxetine is administered at a daily dose ranging from about 30 to about 120 mg, venlafaxine is administered at a daily dose ranging from about 37.5 to about 375 mg, desvenlafaxine is administered at a daily dose ranging from about 25 to about 200 mg, milnacipran is administered at a daily dose ranging from about 12.5 to about 200 mg, and levomilnacipran is administered at a daily dose ranging from about 20 to about 120 mg. In an embodiment, the foregoing amounts are relative to the free base of the indicated compound. In an em bodiment, these amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. The present disclosure further relates to a method of treating a subject having pain comprising administering orally to a patient in need thereof the base compound or a pharmaceutically acceptable salt thereof during an acute induction phase of treatment at a dosage ranging from about 40 mg to about 360 mg relative to the base compound or at an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 hmg / mL to about 3,600 h ng / mL or a Cmax ranging from about 72 ng / mL to about 540 ng / mL at treatment intervals ranging from every other week to three days a week for a period of about four to about six weeks. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered at a dosage range of about 40 to about 180 mg relative to the base compound or in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h ng / mL to about 2,100 hng / mL or a Cmax ranging from about 72 ng / mL to about 330 ng / mL during the acute induction phase of treatment. In a further embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered at a dosage range of about 60 to about 140 mg relative to the base compound or in amount sufficient to achieve in the plasma of the subject an AUC ranging from about 550 h ng / mL to about 1,800 h ng / mL or a Cmax ranging about 110 ng / mL to about 280 ng / mL during the acute induction phase of treatment. In an embodiment, these amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. In an embodiment, the method additionally comprises administering the base compound or a pharmaceutically acceptable salt thereof in an amount ranging from about 40 to about 180 mg relative to the base compound or an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h ng / mL to about 2,100 h ng / mL or a Cmax ranging from about 72 ng / mL to about 330 ng / mL on a weekly to every' other week basis to the patient in need thereof for a period of at least 8 weeks during the maintenance treatment phase. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject during the maintenance treatment phase in an amount ranging from about 40 to about 140 mg relative to the base compound or in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h ng / mL to about 1,800 h ng / mL or a Cmax ranging from about 72 ng / mL to about 280 ng / mL on a weekly to every other week basis. Further, in an embodiment, the base compound or a. pharmaceutically acceptable salt thereof is administered in an amount ranging from about 20 to about 100 mg relative to the base compound or an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 230 h-ng / mL to about 970 h ng / mL or a Cmax ranging from about 39 ng / mL to about 150 ng / mL on a weekly to daily basis to a patient in need thereof for a period of at least eight weeks during the maintenance treatment phase. Further, in another embodiment the base compound or a pharmaceutically acceptable salt thereof is administered to the patient in an amount during the maintenance treatment phase ranging from about. 40 to about 80 mg relative to the base compound or in an amount sufficient to a achieve in the plasma of the subject an AUC ranging from about 390 h ng / mL to about 760 h ng / mL or a Cmax ranging from about 72 ng / mL to about 130 ng / mL on a weekly to daily basis. In an embodiment, these amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. In an embodiment, the pain is chronic pain or neuropathic pain. In another embodiment, the pain is chemotherapy induced neuropathy. In a further embodiment, the treatment results in a decreased intake of opioids by the patient. In an embodiment, the present disclosure relates to a method of treating a patient having pain comprising administering the base compound or a pharmaceutically acceptable salt thereof concurrently with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor to a patient, in need thereof on a daily basis, wherein the base compound or a pharmaceutically acceptable salt thereof is administered at a dosage level in an amount ranging from about 20 mg to about 100 mg relative to the base compound or in an amount per day in an amount sufficient to achieve in the plasma an AUC ranging from about 230 hng / mL to about 970 h ng / mL or a Cniax ranging from about 39 ng / mL to about 150 ng / mL on a weekly to daily basis to a patient in need thereof for a period of at least eight weeks during the maintenance treatment phase. Further, in another embodiment the base compound or a pharmaceutically acceptable salt thereof is administered to the patient in an amount during the maintenance treatment phase ranging from about 40 to about 80 mg relative to the base compound or in an amount sufficient to a achieve in the plasma of the subject an .AUC ranging from about 390 h-ng / mL to about 760 h-ng / mL or a Cmax ranging from about 72 ng / mL to about 130 ng / mL on a weekly to daily basis. In an embodiment, these amounts are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. In an embodiment, the daily dose of base compound or a pharmaceutically acceptable salt thereof is administered as a single unit dose. In an embodiment, the present disclosure relates to a dosing kit comprising unit doses of a first pharmaceutical composition comprising base compound or a pharmaceutically acceptable salt thereof and a first pharmaceutical carrier therefor and unit doses of a second pharmaceutical composition comprising a selective serotonin reuptake inhibitor or a serotoninmorepinephrine reuptake inhibitor and a second pharmaceutical carrier therefor and instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to a patient suffering from a psychiatric disorder or pain. In a further embodiment, the present disclosure is directed to a pharmaceutical composition in solid dosage form comprising a first component of about 20 to about 100 mg of the base compound or a pharmaceutically acceptable salt thereof relative to the base compound and a second component that is one of the following.' about 10 to about 80 rag of fluoxetine, about 10 to about 60 mg of paroxetine, about 10 to about 40 mg of citalopram, about 5 to about 20 mg of escitaiopram, about 25 to about 300 mg of fluvoxamine, about 50 to about 200 mg of sertraline, about 5 to about 20 mg of vortioxetine, about 30 to about 120 mg of duloxetine, about 37.5 to about 375 mg of venlafaxine, about 25 to about 200 nig of desvenlafaxine, about 12.5 to about 200 mg of milnacipran, or about 20 to about 120 mg of levomilnacipran, along with a pharmaceutical carrier therefor. In an embodiment, the foregoing amounts are relative to the free base of the indicated compound. In a further embodiment, the pharmaceutical composition comprises a first component comprising about 20 to about 140 nig of the base compound or a pharmaceutically acceptable salt thereof relative to the base compound and a second component comprising one or more of the following: about 10 to about 80 mg of fluoxetine, about 10 to about 60 mg of paroxetine, about 10 to about 40 mg of citalopram, about 5 to about 20 mg of escitalopram, about 25 to about 300 mg of fluvoxamine, about 50 to about 200 mg of sertraline, or about 5 to about. 20 mg of vortioxetine, along with a pharmaceutical carrier therefor. In an embodiment, the foregoing amounts are relative to the free base of the indicated compound. In another embodiment, the pharmaceutical composition comprises a mixture of two or more components, wherein the first component comprises about 20 to about 100 mg of the base compound or a pharmaceutically acceptable salt thereof relative to the base compound and the remaining component(s) comprises at least one of the following: about 30 to about. 120 mg of duloxetine, about 37.5 to about 375 mg of venlafaxine, about 25 to about 200 mg of desvenlafaxine, about 12.5 to about 200 mg of milnacipran, or about 20 to about 120 mg of levomilnacipran, along with a pharmaceutical carrier therefor. In an embodiment, the foregoing amounts are relative to the free base of the indicated compound. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof rnay be administered as an IV bolus or short infusion of, for example, less than or equal to about 30 minutes in one embodiment, and in another embodiment, less than or equal to about 15 minutes, for a time and dosage effective to treat the psychiatric disorder or pain. In an embodiment, in the acute induction phase of treatment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 13 to about 120 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / tnL to about 540 ng / ml., In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 13 to about 60 mg relative to the base compound or in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL. In a further embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered as an IVbolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 20 to about 47 mg relative to the base compound or in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 110 ng / mL, to about 280 ng / mL. The base compound is administered to the subject in treatment intervals ranging from every other week to three days a week until symptoms from the psychiatric disorder or pain are in remission or sufficiently improved. In an embodiment, the acute induction phase of treatment lasts for about 4 to about 26 weeks, and in another embodiment for about 4 to about 12 weeks, and in another embodiment for about 4 to about 6 weeks, and in another embodiment for about 2 to about 4 weeks. At the conclusion of the acute induction phase, the maintenance treatment phase optionally commences, wherein the objective is to maintain the remission or improvement of the neuropsychiatric or pain symptoms. The base compound or a pharmaceutically acceptable salt thereof is administered as an IV bolus or short infusion in less than or equal to about 15 minutes in amount ranging from about 13 mg to about 60 mg relative to the base compound or in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to even? other week basis for a period of at least 8 weeks, or in another embodiment up to 52 weeks, or until the conclusion of the maintenance treatment phase. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered as an IV bolus or short infusion in less than or equal to about 15 minutes to the patient during the maintenance treatment phase in an amount ranging from about 13 mg to about 47 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL. In another embodiment, in a different dosage regimen for the maintenance treatment phase, the base compound or a pharmaceutically acceptable salt thereof is administered as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 7 mg to about 33 mg relative to the base compound or in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / mL. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to daily basis for a period of at least 8 weeks and in an embodiment, up to 52 weeks, or until the conclusion of the maintenance treatment phase. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered as an IV bolus or short infusion in less than or equal to about 15 minutes to the patient during the maintenance treatment phase in an amount ranging from about 13 mg to about 27 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 130 ng / mL. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 40 to about 80 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 150 ng / mL to about 450 ng / mL. In an embodiment, the listed doses of base compound or a pharmaceutically acceptable salt thereof to be administered as an IV bolus or short infusion in less than or equal to about 15 minutes and corresponding Cmax values are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. By using an IV bolus or short IV infusion, compared to oral administration at the same dose, a higher Cmax is achieved at a faster rate and a higher Cmax / AUC ratio is achieved. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof may be administered intramuscularly (IM) at a dosage amount effective to treat the psychiatric disorder or pain. In an embodiment, it is administered in one dosage. In an embodiment, in the acute induction phase of treatment, the subject suffering from a psychiatric disorder or pain is administered the base compound or a pharmaceutically acceptable salt thereof IM. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 20 to about 180 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 540 ng / mL. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered is in an amount ranging from about 20 to about 90 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL, to about 330 ng / mL during the acute induction phase of treatment. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 30 to about 70 mg relative to the base compound, and in another embodiment, the base compound or a. pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 110 ng / mL to about 280 ng / mL. The base compound or a pharmaceutically acceptable salt, thereof is administered to the subject in treatment intervals ranging from every other week to three days a week until the psychiatric disorder or pain are in remission or sufficiently improved. In an embodiment, the acute induction phase of treatment lasts for about 4 to about 26 weeks, and in another embodiment for about 4 to about 12 weeks, and in another embodiment for about 4 to about 6 weeks, and in another embodiment for about 2 to about 4 weeks. At the conclusion of the acute induction phase, the maintenance treatment phase optionally commences, wherein the objective is to maintain the remission or improvement of the neuropsychiatric or pain symptoms. The base compound or a pharmaceutically acceptable salt thereof is administered to the subject IM in an amount ranging from about 20 to about 90 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL. In another embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to every other week basis for a period of at least 8 weeks or in an embodiment, up to 52 weeks, or until the conclusion of the maintenance treatment phase. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered IM to the patient during the maintenance treatment phase in an amount ranging from about 20 to about 70 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL, In another embodiment, in a different dosage regimen for the maintenance treatment phase, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject IM in an amount ranging from about 10 to about 50 mg relative to the base compound and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / mL. In another embodiment, the base compound or a pharmaceutically acceptable salt, thereof is administered in the above-indicated amount during the maintenance treatment phase to the subject on a weekly to daily basis for a period of at least 8 weeks, or in an embodiment, up to 52 weeks, or until the conclusion of the maintenance treatment phase. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the patient IM during the maintenance treatment phase in an amount ranging from about 20 to about 40 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a (4,.., ranging from about 72 ng / mL to about 130 ng / mL. In an embodiment, the base compound or a pharmaceutically acceptable salt thereof is administered to the subject IM in an amount ranging from about 60 to about 120 mg relative to the base compound, and in another embodiment, in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 150 ng / mL to about 450 ng / mL. In an embodiment, the listed doses of base compound or a pharmaceutically acceptable salt thereof to be administered by IM injection and the corresponding values of Cmax are for an approximately 65 to approximately 80 kg person, e.g., about 70 kg person. By using an IM injection, compared to oral administration at the same dose, a higher Cmax is achieved at a faster rate and a higher Cmax / AUC ratio is achieved. The following examples further illustrate the subject matter of the present disclosure. EXAMPLES A. Examples with Human Subjects in Phase 1 Studies 1. EXAMPLES W m< SI NGLE ASCEN DI NG DOSE The examples that follow are part of a Single Ascending Dose (SAD) study on 6 groups of healthy adult volunteers, wherein each group consisted of eight people. Six members of each group each received single oral doses of base compound, either 20 mg, 60 mg, 100 mg, 140 mg, 220 mg, or 360 mg throughout the trial, while two members of each group received single oral doses of placebo. In addition, a Multiple Ascending Dose (MAD) study was conducted, in which there were 2 groups of 12 subjects, where 9 participants of each group received 4 oral doses of base compound (either 140 or 220 mg) every other day for seven days, and 3 participants of each group received oral doses of placebo at the same time points. To assess food effects, an additional 12 subjects were studied in a crossover manner, where 100 mg of base compound or placebo was orally administered and the participant was either fed or fasted for a prescribed period of time, and then after a. washout period, administered the treatment they did not previously receive. The various pharmacodynamic measures recorded are outlined in FIG. 17. EXAMPLE 1 Human Pharmacokinetics in the SAD Study The following example describes a double-blind, placebo-controlled human trial to evaluate the safety', pharmacokinetics, and pharmacodynamic effects of single doses of base compound administered orally. The study was conducted on human subjects ranging in age from 18 to 50 years with a mean age of 25.2 years, a mean body mass of 71.1 kg, and a mean body mass index (BMI) of 22.7 kg / m2, ranging from 19 to 31 kg / m2. There were a total of 48 subjects tested, half of which were female and 44 of which were white. They were divided into 6 groups of 8 subjects, wherein 2 subjects in each group received placebo and the other 6 subjects in each group received a. single oral dose of base compound at the following dose levels: 20 mg, 60 mg, 100 mg, 140 mg, 220 mg, or 360 mg. The doses indicated are on the basis of free base compound and corrected for salt counterion mass. Blood \vas drawn from each subject at multiple time points post dose, viz., 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 30 hours after its administration, processed to plasma by standard methods, and analyzed for base compound using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Figure 1A shows the plasma concentration of base compound over time as a linear measurement and Figure IB shows a semi-log measurement. The semi-log measurement is traditionally shown as dose-proportional increases, such as observed in Figure 1B, and demonstrate parallel lines between the different drug doses. The results shown in Figures 1A and IB were obtained from the single ascending dose (SAD) trial of the Phase 1 protocol of base compound administered orally in contrast to typical intravenous infusion with the NMD A antagonist ketamine or intranasal administration of the NMDA antagonist esketamine (S-ketamine). With respect to the administration of base compound, from the graphs, it was noted that there was an increased density during the initial few hours of base with respect to the plasma concentration affecting the pharmacokinetic parameters (especially the peak concentration (CmaK) and area under the curve 0-24 h (AUCo-24h) and half-life of the drug (t 1 / 2). The values of area under the plasma concentration versus time curve from time 0 to 24 hours post dose (AUCo-m) and maximum plasma concentration (Cmax) for each cohort receiving base compound are provided in Table 1 below. Table 1. Human Pharmacokinetic Parameters of Base Compound in Plasma Base Compound Dose (mg) n Mean AUCo-w (h*ng / mL) AtC.?.t cv% Maximum Individual AUCo-24 (h*Fja / mL) Mean (ng / mL) C™, cv% Maximum Individual Cmax (og / ml.) Mean (b) Median tmax (h) 20 6 227 20.2 273 39.17 14.5 47.7 4 37 60 6 554 14.3 676 105.0 12.7 122 4.41 1.5 100 A 966 40.2 1598 153.5 20.0 205 4.56 1.5 140 6 1762 23.3 2218 276.7 16.1 353 4.0 J 2 220 6 2428 27.1 3558 381.8 13.3 434 3.95 2.5 360 6 3587 IS 2 6588 540.8 46.7 980 3 77 1.5 Abbreviations: AUC0.24 = area under the plasma concentration versus time curve from time 0 to 24 hours; Cmax maximum plasma concentration, CV% = coefficient of variation, ti,2 = halflife; tmax = time of maximum concentration. As shown in Table 1, the coefficient of variation (CV%) for the AUC0-24 was under 27.1% in 4 of the 6 groups and was 40.2% and 48.2% for the 100 and 360 mg groups, respectively. The CV% for the Cmax was <20% for 5 of the 6 groups and was 46.7% for the 360 mg group. The half-life (tj / 2) was 4.37 to 4.63 hours for the 20 to 140 mg groups while being slightly less (3.95 and 3.77 hours) for the 220 and 360 mg groups. The median time to reach maximum concentration (tmax) values ranged from 1 to 2.5 hours across groups. Regarding safety, there were no deaths, or serious or severe treatment emergent adverse events (TEAE) in any of the groups. A dose-dependent increase in TEAEs occurred through the 220 mg dose; with most TEAEs categorized as mild. EXAMPLE 2 Human Body Sway Measurements in the SAI) Study The body sway measurement provides an objective assessment of postural stability and ataxia by measuring body movements in a single plane. Methods. The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the human subjects as described in Example 1 and Figure 17, Ai 1 hour, 3 hours, 8 hours and 24 hours after administration of the base compound, body sway was measured with a pot string meter (celesco) based on the Wright ataxiameter. With a string attached to the waist, all body movements over a period of 2 minutes were integrated and expressed as mm sway. Subjects were instructed to wear a pair of comfortable, low-heeled shoes on each session. Before starting a measurement, subjects were asked to stand still and comfortably, with their feet approximately 10 cm apart and their hands in a relaxed position alongside the body and eyes closed. Subjects were not allowed to talk during the measurement. Body sway was recorded in all subjects according to the following methods, with the results summarized in Figure 2. Results. Body sway measurements over time following administration of different dose levels of base compound are presented in Figure 2. Up to doses of 100 mg, body sway induced by the base compound did not exceed pre-dose values. At 140 mg and 220 mg, minimal increases at 1.5 h and 3.5 hours post drug administration were noted. At the high dose of 360 mg, a large increase in body sway was observed at these two time points post drug administration but had returned to near baseline by 8 h post dose. Collectively, these findings suggest that doses of base compound of 220 mg or lower induce minimal to no ataxic side effects and may be the most suitable doses for therapeutic use. EXAMPLE 3 Human Dissociative Effects in the SAD Study Dissociative effects of channel blocking NMD A receptor antagonists were noted during the development of these drugs as general anesthetics in the 1960s when subjects would experience derealization, depersonalization, and amnesia when coming out of frank anesthesia. The most widely used scale to measure dissociative symptoms is the Clinician-Administered Dissociative States Scale (CADSS), which includes dissociative effects (derealization, depersonalization, and amnesia) using the Clinician Administered Dissociation Symptom Scale. This 28-item scale contains both subjective and objective items that are scored (0 to 4 for each item) by an experienced clinician. The CADSS developers identified a total CADSS score of greater than 4 at any timepoint to be abnormal. Dissociation was quantified in all subjects using the CADSS, with the mean CADSS total score results summarized in Figure 3. Methods. The 23-item CADSS scale sums together the three sub-scales of derealization, depersonalization, and amnesia to arrive at the Total CADSS score. The clinician asks 23 questions such as “Do things seem to be unreal to you, as if in a dream?” and scores the response using anchors ranging from 0 (not at all) to an item score of 4 (extreme, e.g., I feel like nothing is real, like I should pinch myself to wake up, or ask someone if this is a dream). While this scale consisting of 23 items was originally developed to measure dissociative states in patients with post-traumatic stress disorder (PTSD) and other dissociative disorders, it has been universally adopted to understand dose (exposure)-dependent dissociative effects of NMD A receptor antagonists. The TEAEs reported by at least one participant in the base compound dose level of the SAD trial from the protocol is based on spontaneous reports to a psychiatric physician or any other clinical staff. The verbatim report from the trial participant is matched to the MedRA hierarchy of adverse events MedRA is the acronym for the Medical Dictionary for Regulatory .Activities that is updated on a regular basis and is accepted by all regulatory authorities for the scoring of adverse events during clinical trials of medications or medical devices. Adverse events (AEs) are recorded from the time of admission to the clinical unit for a trial such as the current one through discharge from the clinical unit and through generally 30 days after administration of the drug. Treatment-emergent AEs (TEAEs) are AEs reported by the participant after administration of a trial treatment, in this case, for example, base compound or placebo. As discussed above, the spontaneous verbatim report is matched to the Preferred Term from the MedRA hierarchy which most accurately describes the event. Each preferred term is listed under broader System Organ Class (SOC) terms such as Psychiatric Disorders or Nervous System Disorders which comprised a majority of TEAEs for the SAD, MAD and Food studies of the Phase 1 protocol. An adjudication meeting was held prior to database lock to ascertain that the verbatim listing was matched to the best Preferred Term and SOC category. Thus, slow response to stimuli could be either a subjective report by the participant to an observer or it could be an objective observation by an observer. TEAEs could also be clinically significant laboratory (hematology or chemistry) reports or clinically abnormal vital signs observed by the clinical staff In the Single Ascending Dose (SAD) trial described in Example 1 and Figure 17, dissociative effects were assessed by an experienced clinician from the reports of healthy male and female volunteers using the CADSS at about 37 min, 2 hours, 3 hours 44 minutes, 6 hours, and 30 hours following administration of placebo and base compound doses of 20-360 mg (20, 60, 100, 140, 220 and 360 mg; 6 participants on active drug at each given dose level). Results. All participants had baseline CADSS total scores of 0, indicating no pre-dose dissociation. At 37 minutes post-dose, no participant in the 20 to 100 nig base compound dose groups had a CADSS total score greater than 4, a criterion used to indicate a clinically significant increase in dissociation. The breakdown of the various specific assessments for the different groups are depicted in Figures 4 and 5. For the 140 mg dose group, 1 out of 6 participants had a CADSS total score of >4 at 37 minutes post-dose. For the 220 and 360 mg doses, 4 of 6 participants had a CADSS total score of >4, indicating that most participants in these groups experienced some dissociation. This rate of CADSS-defined dissociation for these highest 2 dose levels is similar to that reported for esketamine (range of 60% to 84% (Spravato Package Insert)). Mean CADSS scores by timepoint and treatment group are shown in Figure 3. Similar to past observations with ketamine (Fava M et al., Mol Psychiatry, 2020, 25: 1592-1603. doi: 1038 / s41380-018-0256-5), there was a base compound dose-dependent increase in mean CADSS scores at about 30 minutes post dose where mean CADSS total scores for the 220 and 360 mg dose groups were 7.0 (range of 1 to 14) and 19.2 (range of 0 to 43), respectively. In comparison, patients in a Phase 3 study of esketamine nasal spray with an antidepressant displayed an approximate 7-point change from baseline at approximately 40 minutes post esketamine (See, Wajs, et al., J Clin Psychiatry, 81(3) ,12891 (2020); https: / / pubmed.ncbi.nlm.nih.gov / 32316080 / ). For all base compound dose groups, mean CADSS total scores decreased at the 2 h and 3 h 44 min post-dose timepoints. At. 2 h post-dose, 1 out of 6 participants in each of the 100, 140, and 220 mg dose groups had a CADSS total score of >4, with scores of 10, 5, and 9, respectively, and 3 participants in the 360 mg group had a CADSS total score >4, with scores of 22, 26, and 29. The mean CADSS total score for the 360 mg group was 10.0 (range of 0 to 29) at the 2 h post-dose timepoint. Ai 3 h 44 min post-dose, no participants in the 20 to 220 mg groups had a CADSS total score >4 and only 2 participants in the 360 mg group had CADSS total scores of >4, with scores of 12 and 15. At 6 hours post-dose, no participant had a CADSS total score of >4, with all participants having CADSS total scores of 0 except for 2 participants in the 360 mg group who had non-zero CADSS total scores of 1 and 3. At 30 hours post dose, all participants had CADSS total scores of 0. Collectively, these finding suggest that doses of base compound lower than 220 mg induce reduced dissociative side effects compared to ketamine and esketamine at typical antidepressant doses and therefore, may be the most suitable doses for therapeutic use. Figure 7 shows the dose-dependent and time-dependent effects of base compound at increasing dissociation in the SAD trial. As the graph shows, there are minimal dissociative effects of base compound over the expected therapeutic dose range of 60-140 mg. Figure 6 provides a graphical depiction of the percentage of human subjects who were orally administered base compound exhibiting CADSS greater than 4 at any time following base compound administration. CADSS scores greater than 4 are considered a clinically significant endpoint. This fi gure shows dose-dependent effects of base compound at increasing dissociative effects (derealization, depersonalization, and amnesia) using the Clinician Administered Dissociation Symptom Scale. This figure shows the aggregated incidence of base compound (20360 mg) at inducing a CADSS score > 4 at any time point where the results of the SAD, MAD and food effect studies from the Phase 1 protocol have been combined. The SAD trial examined doses of 20, 60, 100, 140, 220 and 360 mg while the MAD trial examined doses of 140 and 220 mg. The food effect trial examined a dose of 100 mg base compound in a crossover fashion under both fed and fasted states. The SAD and MAD studies were all conducted in the fasting condition. Of note, the incidence of abnormal dissociative scores as determined by the CADSS instrument was none to minimal (26.7) over the expected therapeutic dose range of 60-140 mg. In contrast, the esketamine package insert for MDD and the Spravato Package Insert of esketamine notes that the incidence of dissociative effects is approximately 60-84% for therapeutic doses (56 and 84 mg intranasal esketamine). EXAMPLE 4 Human EEG in the SAD Study Resting-state electroencephalography (EEG) is very sensitive to central actions of pharmacological substances. For this reason, phartnaco-EEG (pEEG) has become an established method to assess drug effects on central nervous system (CNS) functioning. The measurement and analysis of EEG activity in pharmacological research generally comprises a number of electrodes to obtain an impression of'overall' cerebral EEG activity. The time-domain recordings are transformed into the frequency domain and changes in EEG power in certain frequency bands are then quantified. The frequency bands of interest include the delta (3), theta (9), alpha (a), beta (P), and gamma (y) bands. In the Phase 1 clinical trial described in Example 1, EEG activity was recorded in all subjects according to the following methods, with the results summarized in Figure 7 A, 7B, 7C, and 7D. Methods. For the resting-state EEG setup, the TMSi EEG recording equipment was used. 21 electrodes were embedded in an EEG cap according to the international 10-20 system. The scalp electrode impedance was kept below N1 The ground electrode was placed at AFz EEG location. All signals were sampled at a sampling rate of 1024 Hz and are filtered prior to storage using a first order recursive high-pass filter with a cut-off frequency at 0.1 Hz. Digital markers were recorded by the amplifier indicating the start and end of each eye state. Subjects were seated in a comfortable position and were looking towards the wail. Subjects were instructed not to stare, to limit their head and eye-movements, and to suppress eye-blinks. Each recording employed alternating periods with eyes opened (Figure 8A and Figure 8B) and closed (Figure 8C and Figure 8D) with a duration of 64-seconds per period. This is repeated 5 times, resulting in 10 minutes of usable EEG. Between eyes opened and closed sessions, subjects were given some time to get adjusted to the ‘new7’ lightning conditions. This is especially important when transitioning from closed to opened eyes. Subjects were informed to close or open their eyes based on custom scripts that also sent trigger information to the EEG recording device. Analysis of the EEG recordings was performed automatically after the measurement using custom scripts written in Matlab by Mathworks. EEG recordings were high-pass filtered at 0.5 Hz to remove DC offset. Notch filter at 50 Hz was applied to remove line noise. Bad channels were identified as channels with low correlation with their neighboring channels. Identified bad channels were then interpolated as an average of their neighboring channels. All EEG signals were re-referenced by subtracting the average EEG signal obtained from all EEG electrodes. Noisy epochs in signals were detected as epochs that crossed variance estimated from baseline recording using predefined threshold and were excluded from further analysis. EEG signals were separately normalized by dividing signals by their root-mean-square (RMS) value obtained from the baseline recording. EEG signal power was computed by convolving EEG signal with a group of log-spaced complex MorJet wavelets in the frequency range of 1-100 Hz and scaling factor fo / sr = 8 followed by squaring the result. Pow7er values were separately averaged for eyes open and eyes closed conditions across consecutive timepoints. Power values were further averaged across canonical EEG bands including delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-25 Hz), slow gamma. (GammaS, 30-50 Hz), and fast gamma (GammaF, 65-95 Hz) to obtain band-specific spectral averages. Finally, EEG band-specific power values were averaged across all electrodes to obtain single value of EEG band-specific power value for each subject, time point, EEG band and state (eyes open or eyes closed). The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the human subjects as described in Example I and Figure 17. The EEG measurements using the method described hereinabove were taken 2 hours before administration, 1 hour before administration, 1 hour after administration, 3 hours after administration and 8 hours after administration of base compound or placebo. Results. The EEG results at different dose levels in the eyes open state are presented in Figures 8A, 8B, 8C, and 8D. Figure 8A depicts the EEG results when the eyes are open, which are graphically depicted in Figure 8B, while Figure 8C depicts the results when the eyes are closed, which are graphically depicted in Figure 8D. The base compound induced dosedependent effects across several frequency bands, with the most prominent effects seen in the alpha (decreased power) and gamma (increased power) frequency bands. Interestingly, effects on alpha power were apparent at doses as low as 60 mg, while dissociative effects as quantified by the CADSS (see Example 3) and ataxia as quantified by body sway (see Example 2) were absent at this dose. At intermediate doses from 100 to 220 mg, effects on alpha power were even stronger and some changes in gamma power were observed, while dissociative effects and ataxia remained limited. Strong dissociative and ataxic effects were only observed at the high dose of 360 mg, where dramatic increases in gamma power were also seen on EEG. Overall, these findings, in combination with those of Examples 2 and 3, demonstrate that the base compound can be dosed at levels sufficient to modulate brain activity while inducing limited dissociative and ataxic side effects. .Additional examples are provided to support the efficacy of the compounds of the present disclosure for treating psychiatric diseases. EXAMPLE 5 Real Time Intensity Scale in the SAD Study The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the subjects as described in Example 1 and Figure 17. The subjects answered questions which were specifically designed to monitor the trajectory of psychotomimetic drugs like NMDA receptor antagonists or psychedelic 5-HT2A receptor agonists after the administration of the drugs, and subjects’ reported effects on Bodily Intensity, Visual Intensity, and Emotional-Metacognitive intensity are monitored on a 10 point scale (Onot at all; 10 exiremcri } that are recorded by a clinician so that that subject only has to verbally report the drug’s intensity of effects at that time. The Real Time Intensity score is recorded by a clinician from the verbal report of the subject; the subject does not have to read the question or make a motor response on paper or electronic device to record their answer. Thus, the fidelity of the measurement is not as affected by sensory / motor impairment at higher doses of the base compound. The Real Time Intensity Total Score is simply a mean of the scores on the Bodily, Visual, and Emotional-Metacognitive intensity score. In the SAD trial, these measurements were recorded at 15 and 30 min, and 1, 2, 3, 4, 6, 8, 12, and 24 h post-dose. The results are graphically depicted in Figure 9. As shown by the graph, oral administration of base compound increased the patient reported Real Time Intensity Scale for Total Score using healthy male and female subjects described in Example 1 and Figure 17 in the single ascending dose (SAD) trial. The base compound increased the Total Score in a dose-dependent manner. However, relatively modest effects were observed for doses of 100 mg or less. EXAMPLE 6 5D-ASC Score in the SAD Study Figure 10 shows dose-related increases on the major 5 dimensions of the 5-Dimensional Altered States of Consciousness (5D-ASC) scale. This scale consists of 94 questions that are designed to quantify alterations of consciousness whether those effects are induced by environmental perturbations (e.g., sleep deprivation) or drugs such as NMDA receptor antagonists or psychedelic 5-HT?a receptor agonists. These questions measure the 5D-ASC and is typically provided at a prescribed period of following the resolution of drug effects. In the case of base compound of the SAD trial described herein, the 5D-ASC were measured approximately 8 hours following administration of the drug. The 5 major dimensions of this instrument are anxious ego dissolution, auditory alterations, oceanic boundlessness, reduction of vigilance and visionary restructuralization. Of note, dimensions such as anxious ego dissolution and oceanic boundlessness are especially related to dissociative effects of NMDA receptor antagonists that led to them being described as dissociative anesthetics as very high doses led to anesthesia while lower doses led to dissociative effects as drag concentrations rose or as drag concentrations decreased while patients anesthetic effects wore off. The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the subjects as described in Example 1. The subjects in each group were evaluated at approximately 8 hours following administration of the drug. The results are depicted in Figure 10. EXAMPLE 7 VAS Alertness in the SAD Study Another dissoci ative effect from the administration of base compound at the various dosages was measured. It is the Bond and Lader VAS Alertness factor. This test was given to each subject in each of the groups, including the groups to which placebo were administered. This test is self-administered and evaluates 16 dimensions of mood: Alert-Drowsy, Calm-Excited, Strong-Feeble, Muzzy-Cl ear headed, Well Coordinated-Clumsy, Lethargic-Energetic, Contented-Discontented, Troubled-Tranquil, Mentally Slow-Quick Witted, Tense-Relaxed, Attentive-Dreamy, Incompetent-Proficient, Happy-Sad, Antagonistic-Friendly, Interested-Bored, and Withdrawn-Social. Each of the subjects in each group is required to indicate by marking on a 100 mm line the extent that the above-listed dimension of mood is appropriate at the time of the measurement, which, in this trial, is 2 hours before administration of the base compound, at the time of the administration of the base compound, 2 hours after administration of the base compound, 3 hours after administration of the base compound, 4 hours after administration of the base compound, 6 hours after administration of the base compound, 8 hours after administration of the base compound, and 24 hours after administration of the base compound. From the individual responses, the values on the VAS alertness, consisting of alertness, contentment and calmness, is determined by a trained professional in the psychiatric field, such as a trained clinician, trained technician, trained doctor, and the like. The mean of the results is determined for each subject in each of the groups. The group administered the placebo also participated in this test for comparative purposes. The results are depicted in Figure 16. The results show that the base compound increases sedation of the subject relative to that of the subject to which placebo was administered. EXAMPLE S Saccadic Peak Velocity in the SAD Study The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the subjects as described in Example I and Figure 17 and its effect on saccadic movement and saccadic peak velocity (“SPV”) and the change from baseline (“CFB”) was measured. A saccade is a rapid, conjugate, eye movement that shifts the center of gaze from one pan of the visual field to another. Saccades are mainly used for orienting gaze towards an object of interest. Saccades may be horizontal, vertical, or oblique. Saccades are rapid, ballistic movements of the eye that abruptly changes the point of eye fixation. For example, saccadic movement ranges in amplitude from the small movements made while reading, for example, to the much larger movements made while gazing around a room. The effect of saccadic peak velocity is depicted in Figure 11. This figure depicts the change from baseline of the saccadic peak velocity at the various oral dosages over time. The saccadic peak velocity was measured 1 hour before administration, at the time of administration, 1 hour after administration, 3 hours after administration, 8 hours after administration and 24 hours after administration of the base compound or placebo. This measurement, was effected by techniques known in the art. As shown by the data, there was none to modest, decreases from 60-140 mg of base compound when orally administered. The 360 mg dose shows the greatest deviation from baseline and is comparable to slightly higher exposures relative to therapeutic esketamine exposure which is administered intravenously. EXAMPLE 9 Systolic Blood Pressure in the SAD Study The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the subjects as described in Example 1 and Figure 17 and the electrocardiogram was taken of the human subject 24 hours prior to oral administration of the base compound, 2 hours prior to oral administration of the base compound, at the administration of the base compound, 2 hours after administration of the base compound, 6 hours after administration of the base compound, 8 hours after administration of the base compound and 24 hours after administration of the base compound. Figure 12 shows dose-dependent and time-dependent effects of base compound at increasing systolic blood pressure (SBP) from baseline values (-24 h and -2 h prior to drug administration) in the SAD trial protocol. Triplicate vital sign measurements (SBP, diastolic blood pressure, pulse, temperature, respiration rate) were obtained after 5 min rest in the supine position. Figure 13 shows generally dose-related increases in blood pressure 30 min after base compound was orally administered. Of note is that increases in SBP in the lower end of the expected therapeutic dose range (60-140 mg) was generally improved compared to increases in SBP with respect to esketamine nasal administration. Due to the number of measures included in the SAD trial, the vital signs were only singleton measurements, rather than triplicate measures which would decrease variability. EXAMPLE 10 QTcF and Heart Rate in the SAD Study The base compound was orally administered at dosages of 20 mg, 60 mg, 100 mg, 140 mg, 220 mg or 360 mg to the subjects as described in Example 1 and the electrocardiogram was taken of the human subject. 24 hours prior to oral administration of the base compound, 2 hours prior to oral administration of the base compound, at the administration of the base compound, 2 hours after administration of the base compound, 6 hours after administration of the base compound, 8 hours after administration of the base compound and 24 hours after administration of the base compound. The effect on QT interval on an electrocardiogram was measured. The QT interval is a measurement that is made on an electrocardiogram which is used to evaluate the electrical properties of the heart. It is determined from the beginning of the Q wave to the end of the T wave and it approximates the time that it takes from the start, of the cardiac ventricles to contract until they relax. If the QT interval is abnormally long or short in a subject, the subject has an increased risk of abnormal heart rhythms and sudden cardiac arrest. Figures 15 and 14, respectively show dose-dependent and time-dependent effects, respectively, of base compound at increasing heart rate (beats per minute, bpm) and increasing QTcF (QT interval of the 12 lead ECG corrected for heart rate by the Fredericia’s formula) in the SAD trial of the Phase 1 protocol. Baseline 12 lead electrocardiograms (ECGs) were obtained at -24 and -2 h prior to drug administration. Single 12-lead ECGs w7ere obtained at 30 min, 2, 6 and 24 h following drug administration to measure ECG parameters of heart rate, PR interval, QRS interval, and QTcF. Of note, there were not clinically important increases in QTcF over the expected base compound therapeutic dose range of 60-140 mg. Modest increases in heart rate were noted over this therapeutic dose range, unlike the clear increase in heart rate at a high dose of 360 mg. More specifically, as shown by Figure 14, QTcF was increased by 13.7 ms after administration of 360 mg of base compound as compared to placebo, while QTcF was increased by 4.7 ms after administration of 140 mg of base compound as compared to placebo (singleton ECGs). Figure 15 shows that the heart rate was increased by 14.3 beats per minute after administration of 360 mg of base compound as compared to placebo, while the administration of 140 mg of base compound decreased the heart rate by 1.2 beats per minute as compared to placebo. 2. EXAMPLES RELATING TO A MULTIPLE ASCENDING DOSE STUDY The following examples relate to the Multiple Ascending Dose (MAD) study, in which there were 2 groups of 12 healthy adult volunteers, which were mostly male [70.8%] and white [70.8%]. Nine participants in each group received a single oral dose level (140 mg or 220 mg) of base compound and 4 doses were administered ever) / other day for seven days, and 3 participants in each group received oral doses of placebo at the same time points. The doses indicated are on the basis of free base compound and corrected for salt counterion mass. Unless indicated to the contrary, these are the subjects in the MAD studies. EXAMPLE 11 Human Pharmacokinetics in the MAD Study Blood was drawn from each subject in the MAD trial at multiple time points post dose on days I and 7 of the MAD trial, viz., I hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours and 96 hours after administration of base compound to the subject, processed to plasma by standard methods, and analyzed for base compound using a validated liquid chromatography-tandem mass spectrometry’ (LC-MS / MS) method. Figure 18A shows the plasma concentration of base compound over time on the first day of administration as a linear measurement, and Figure 18B shows a semi-log measurement of the data in Figure 18A. On the seventh day, the plasma concentration of base compound over time was measured and recorded. Figure 18C show's the plasma concentration of base compound over time on the seventh day of administration as a linear measurement and Figure 18D shows a semi-log measurement of the data in Figure 18C. The semi-log measurement is traditionally shown as dose-proportional increases, such as observed in Figures 18B and 18D, and demonstrate parallel lines between the different drug doses. With respect to the administration of base compound from the graphs, it was noted that there was an increased density during the initial few hours of the administration of base compound with respect to the plasma concentration. The data shows that there was no evidence of accumulation with every other day dosing over the seven days, EXAMPLE 12 Human EEG in the MAD Study Resting-state electroencephalography (EEG) is very sensitive to central actions of pharmacological substances. For this reason, pharmaco-EEG (pEEG) has become an established method to assess drug effects on central nervous system (CNS) functioning. The measurement and analysis of EEG activity in pharmacological research generally comprises a number of electrodes to obtain an impression of'overall' cerebral EEG activity. The time-domain recordings are transformed into the frequency domain and changes in EEG power in certain frequency bands are then quantified. The frequency bands of interest include the delta (S), theta (0), alpha (a), beta (P), and gamma (y) bands. In the Phase 1 clinical trial described in Example 12, EEG activity was recorded in all subjects in the MAD trial on the first day and on the seventh day according to the following methods, with the results summarized in Figure 19A, 19B, 19C, and 19D. Methods. For the resting-state EEG setup, the TMSi EEG recording equipment was used. 21 electrodes were embedded in an EEG cap according to the international 10-20 system. The scalp electrode impedance was kept below 5kD. The ground electrode was placed at AFz EEG location. All signals were sampled at a sampling rate of 1024 Hz and are filtered prior to storage using a first order recursive high-pass filter with a cut-off frequency at 0.1 Hz. Digital markers were recorded by the amplifier indicating the start and end of each eye state. As described above, subjects received base compound of 140 mg and 220 mg on days 1, 3, 5 and 7. The EEG were measured only on days 1 and 7. Subjects were seated in a comfortable position and were looking towards the wall. Subjects were instructed not to stare, to limit their head and eye-movements, and to suppress eye-blinks. Each recording employed alternating periods with eyes opened on the first day and seventh day (Figure 19A and Figure 19B, respectively) and closed on the first day and seventh day (Figure 19C and Figure 19D, respectively) with a duration of 64-seconds per period. In FIGS. 19A-19D, the number besides placebo (PBO) and active (ACT) indicates the number of subjects. This is repeated 5 times, resulting in 10 minutes of usable EEG. Between eyes opened and closed sessions, subjects were given some time to get adjusted to the ‘new’ lightning conditions. This is especially important when transitioning from closed to opened eyes. Subjects were informed to close or open their eyes based on custom scripts that also sent trigger information to the EEG recording device. Analysis of the EEG recordings was performed automatically after the measurement using custom scripts written in Matlab by Mathworks. EEG recordings were high-pass filtered at 0.5 Hz to remove DC offset. Notch filter at 50 Hz was applied to remove line noise. Bad channels were identified as channels with low correlation with their neighboring channels. Identified bad channels were then interpolated as an average of their neighboring channels. All EEG signals were re-referenced by subtracting the average EEG signal obtained from all EEG electrodes. Noisy epochs in signals were detected as epochs that crossed variance estimated from baseline recording using predefined threshold and were excluded from further analysis. EEG signals were separately normalized by dividing signals by their root-mean-square (RMS) value obtained from the baseline recording. EEG signal power was computed by convolving EEG signal with a group of log-spaced complex Morlet wavelets in the frequency range of 1-100 Hz and scaling factor fo / sr:=: 8 followed by squaring the result. Power values were separately averaged for eyes open and eyes closed conditions across consecutive timepoints. Pow'er values were further averaged across canonical EEG bands including alpha (8-13 Hz) and fast gamma (GammaF, 65-95 Hz) to obtain band-specific spectral averages. Finally, EEG band-specific power values were averaged across all electrodes to obtain single value of EEG band-specific power value for each subject, time point, EEG band and state (eyes open or eyes closed). The base compound was orally administered at dosages of 140 nig or 220 mg to the human subjects. The EEG measurements using the method described hereinabove were taken 2 hours before administration, 1 hour before administration, 1 hour after administration, 3 hours after administration and 8 hours after administration of base compound or placebo. Results. The EEG results at different dose levels in the eyes open state are presented in Figures 19 A, 19B, 19C, and 19D. FIGS 19A and 19B depict the EEG results when the eyes are open on Days 1 and 7 at oral doses of 140 mg and 220 nig, respectively, which are graphically depicted in FIGs. 20A and 20B, while FIGS. 19C and 19D depict the results when the eyes are closed, ’which are graphically depicted in FIGS. 20C and 20D, The data from day 1 in the MAD trial replicate the suppression of alpha activity and enhancement of gamma activity observed int SAD trials. Overall, these findings demonstrate that the base compound can be dosed at 140 and 220 mg, which are levels sufficient to modulate brain activity, while not exhibiting tachyphylaxis or sensitization during the seven-day trial. EXAMPLE 13 Human Dissociative Effects in the MAI) Study Using the methodology of Example 3, dissociative effects were assessed by an experienced clinician from the reports of the human subject in the MAD trial using the CADSS at about 37 minutes, 2 hours, 3 hours 44 minutes, 6 hours, and 30 hours following administration of placebo and base compound doses of 140 mg and 220 mg on day 1, day 3, day 5, and day 7, The results are tabulated in FIG. 21, in which responses regarding many complaints (events) were measured. In particular, the complaints of gastrointestinal disorders, general disorders, nervous system disorders, and psychiatric disorders were tabulated. As shown by the data, there were no SAEs (severe adverse events) or TEAEs (severe treatment emergent adverse effects) were observed, which results are consistent with the results from the SAD trial. Figure 22 provides a graphical depiction of the percentage of human subjects in the MAD trial who were orally administered base compound and exhibited CADSS greater than 4 at any time following base compound administration of 140 mg and 220 mg on day 1, day 3, day 5 and day 7. This figure depicts the dose-dependent effects of base compound at increasing dissociative effects (derealization, depersonalization, and amnesia) using the Clinician Administered Dissociation Symptom Scale. The procedure used is described in Example 3 hereinabove, the contents of which are incorporated by reference, and the CADSS values are the mean of the values obtained from each group of subjects on day 1, day 3, day 5 and day 7 of the trial. As indicated when discussing Example 3, CADSS scores greater than 4 are considered a clinically significant endpoint. This figure shows the aggregated incidence of base compound (at 140 mg and 220 mg) at inducing a CADSS score > 4 on day 1, day 3, day 5, and day 7 of the trial. The data for day 1 replicates the data for day 1 of the SAD trial with respect to the increased incidence in CADSS total scores greater than 4 that were observed when 140 and 220 mg of base compound were administered to the subjects. There was no evidence of tachyphylaxis from the administration of 140 mg of base compound, and little, if any evidence of tachyphylaxis from the administration of 140 mg of base compound. In addition, there was no evidence of sensitization during the trial from day 1 to day 7. Figure 23 A and Figure 23B graphically depicts the real time intensity on a scale from 0 to 10 from the administration of 140 mg and 220 nig of base compound to the human subject in the MAD trial following the procedure of Example 5 on days 1 and 7, respectively. As shown by the data, the base compounds increased the subjects reported real time Intensity total score from oral administration of base compound at 140 mg and 220 mg, respectively. The data for day 1 increasing the total Intensity scores replicates the data observed in the SAD trial. In addition, there is no evidence for tachyphylaxis or sensitization observed during the course of the 7-day trial. Another dissociative effect from the administration of base compound at 140 mg and 220 mg subject was measured. It is the Bond and Lader VAS Alertness factor. This test was given to each subject in the MAD trial who was administered the 140 mg and 220 mg base compound on day 1, day 3, day 5 and day 7 of the trial. The data is obtained on day 1 and day 7 of the MAD trial. This test is self-administered and evaluates 16 dimensions of mood: Alert-Drowsy, Calm-Excited, Strong-Feeble, Muzzy-Clear headed, Well Coordinated-Clumsy, Lethargic-Energetic, Contented-Discontented, Troubled-Tranquil, Mentally Slow-Quick Wilted, Tense-Relaxed, Attentive-Dreamy, Incompetent-Proficient, Happy-Sad, Antagonistic-friendly, Interested-Bored, Withdrawn-Social, Each of the subjects in each group is required to indicate by marking on a 100 mm line the extent that the above-listed dimension of mood is appropriate at the time of the measurement, which is 1 hour before administration of the base compound, at the time of the administration of the base compound, 1 hour after administration of the base compound, 2 hours after administration of the base compound, 3 hours after administration of the base compound, 4 hours after administration of the base compound, 6 hours after administration of the base compound, 8 hours after administration of the base compound, and 24 hours after administration of the base compound. From the individual responses, the values on the VAS alertness, consisting of alertness, contentment and calmness, is determined by a trained professional in the psychiatric field, such as a trained psychiatric clinician, trained psychiatric technician, trained psychiatric doctor, and the like. A mean of the results is determined for each subject in each of the groups. The group administered the placebo also participated in this test for comparative purposes. The results are depicted in Figures 24A and 24B. The data for day 1 replicates the decrease in VAS alertness observed in the SAD trial for the subjects administered base compound at 140 mg and 120 mg. There was no evidence for sensitization from day 1 to day 7 for the subjects who were administered the base compound at 140 and 220 mg doses. EXAMPLE 14 Systolic Blood Pressure in the MAI) Study The base compound was orally administered at dosages 140 mg and 220 mg to the subjects in the MAD trial on days 1, 3, 5, and 7 of the MAD trials, and the electrocardiogram was taken of each of the subjects in each group on days 1 and 7 at 24 hours prior to oral administration of the base compound, 2 hours prior to oral administration of the base compound, at the administration of the base compound, 2 hours after administration of the base compound, 6 hours after administration of the base compound, 8 hours after administration of the base compound and 24 hours after administration of the base compound. A placebo was administered to each subject in the placebo groups and the electrocardiogram was taken of each subject in the placebo group according to the above schedule. Figures 25 A and 25B show dose-dependent and time-dependent effects of base compound at 140 mg and 220 mg at increasing systolic blood pressure (SBP) from baseline values (-24 h and -2 h prior to drug administration) in the MAD trial. Triplicate vital sign measurements (SBP, diastolic blood pressure, pulse, temperature, respiration rate) were obtained after 5 min rest in the supine position. The mean values for each subject at each time interval is determined and plotted on the graph in Figures 25 A and 25B. The data in the MAD trial replicates the increase in systolic blood pressure observed in the SAD trial for 140 and 220 mg dosages. There is no evidence for sensitization for any of the subjects in the groups to which 140 mg and 220 mg of base compound were administered during the 7-day trial. CONCLUSIONS FROM THE MAD STUDY The base compound increases in a dose-proportional manner without evidence for accumulation (4 doses / 7days). The base compound replicates dose-proportional EEG changes with no evidence for tachyphylaxis or sensitization. The base compound replicates dose-proportional increase in dissociative effects without evidence for sensitization. The base compound replicates dose-proportional increases in sedative effects without evidence for sensitization. The base compound replicates dose-proportional increases in systolic blood pressure without evidence of either tachyphylaxis or desensitization. B. Examples with Non-Human Subjects EXAMPLE 15 Forced Swim Test Animals. Male Sprague-Dawley rats, aged 8-10 weeks, were used in the experiments. Animals were housed in groups of 2 under controlled temperature (22 ± 3°C) and relative humidity (30-70%) conditions, with 12-hour light / dark cycles, and with ad libitum food and water. All efforts were made to minimize suffering. Dregs and Dreg Administration. The hydrochloride salt of fo0~2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one, in a saline vehicle, and the positive control desipramine were administered subcutaneously (s.c.), with doses calculated based on the freebase. All compounds were administered at a volume of 5 mL / kg. Test compounds and vehicle were administered 0.5 h after the start of the training swim (Swim 1), which was 23.5 h before the test swim (Swim 2). Desipramine was administered 3 times, at 23.5 h, 5 h, and 0.5 h before the test swim (Swim 2), each time at a dose of 20 mg / kg. Forced Swim Test (FST). Animals were randomized based on body weight to ensure that inter-group variations were minimal and did not exceed ± 20% of the mean body weight across the groups. Group size was n = 10 per treatment. Rats were handled for about 2 min daily for the 5 days prior to the beginning of the experimental procedure. On the first day of the experiment (i.e., Day 0), post randomization, training swim sessions (Swim 1) were conducted between 12:00 and 18:00 h with all animals by placing rats in individual glass cylinders (46 cm tall x 20 cm in diameter) containing 23 - 25 °C water 30 cm deep for 15 minutes. At the conclusion of Swim 1, animals were dried with paper towels, placed in heated drying cages for 15 minutes, and then returned to their home cages. Animals were then administered with the appropriate drug or vehicle treatment(s), as described above. For clarity, a compound administration time of 23.5 h before Swim 2 means 0.5 h after the start of Swim 1 and 0.25 h after the completion of Swim 1 (i.e., immediately after return to the home cage). On Day 1 (i.e., 24 h after start of Swim 1), animals performed the test swim (Swim 2) for a period of 5 min but otherwise under the same conditions as Swim 1. During all swim sessions, the water was changed between each animal. Behavioral scoring was conducted by observers who were blind to the treatment groups. .Animals were continuously observed during Swim 2 and the total time spent engaging in the following behaviors was recorded: immobile, swimming, and climbing. A rat was judged to be immobile when it remained floating in the water without struggling and made only those movements necessary to keep its head above water. A rat was judged to be swimming when it made active swimming motions, more than necessary to merely maintain its head above water (e.g., moving around in the cylinder). A rat was judged to be climbing when it made active movements with its forepaws in and out of the water, usually directed against the walls. Statistical Analysis. Data points are presented as the mean * standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9 or 10. Comparisons between groups were performed using the one-way analysis of variance (ANOVA), followed by Dunnett’s test for comparisons to vehicle. The results are depicted in Figure 26 A. It shows the effect of acute administration of base compound (1-32 mg / kg. s.c.) on immobility time in naive rats tested in the FST 24h after dosing (n>10 / group). A one-way ANOVA revealed a significant main effect of treatment (F(5, 104) = 30.19, / ? < 0.0001). Asterisks indicate a significant difference from the vehicle treated group using Dunnett’s post-hoc test. The active comparator, desipramine (20 mg / kg, s.c.), dosed 3 times (23.5, 4 and 0.5 h) prior to testing also decreased immobility time. These results show that the base compound produced dose-dependent reductions in immobility time in the FST 23.5 hours post dose. All doses significantly reduced immobility time (as determined in independent PK experiments, the lowest interpolated Cmax exposure associated with a significant, reduction in immobility time was 114 ng / mL), with the lowest dose achieving maximal efficacy being 3.2 mg / kg. In the following examples, unless otherwise specified, all experiments used adult male C57BL6 / J mice housed 2-5 / cage, or adult male Sprague-Dawley rats housed 2 / cage. All animals had ad libitum access to food and water and were maintained in a light and temperature-controlled vivarium. All studies with live animals were approved by the ethics committee at the institution where they took place and conform to the standards set forth in the NTH Guide for Care and. Use of Laboratory Animals. EXAMPLE 16 Chronic Mild Stress (CMS) A CMS trial was carried out in male Wistar-Han rats as described in articles by Papp in Eur. J. Pharmacol., 1996, 1996; Papp in Curr. Protoc. Pharmacol., 2012, 57; Wilner et al. in Neurosci Bibehav Rev. 1992, 16, 525-534, Papp et al., JPsychopharmaco!, 2020; 34, 1418-1430 and Papp et al. Curr Protoc. 2023, 3 the contents for conducting this protocol being incorporated by reference. Figure 26B depicts an overview of the experimental schedule for CMS studies. Blue arrows represent weekly sucrose drinking tests (Tuesdays). Green arrows show when animals received weekly treatments (Mondays), The black arrow shows the timing for the EPM (Wednesday), and the grey arrow for the NOR test (Thursday). For each treatment group n=8 rats were exposed to CMS stressors, and n~8 rats were unstressed controls. A second CMS study was conducted to evaluate efficacy of the base compound after oral dosing and the duration of efficacy following a single dose in male Wistar-Kyoto rats (Charles River, Sulzfeld, Germany). Animals in both studies were single housed prior to the onset of stress. The EPM and NOR tests were not performed in the second study. Figure 26C shows the effect of base compound (0.75-9 mg / kg, i.p.) and (rac)-ketamine (10 mg / kg, i.p.) on sucrose intake. Weeks 1 and 2 show the effect of CMS on sucrose intake prior to the initiation of drug treatment. During weeks 3-7, animals were administered base compound, (rac)-ketamine (as a positive control), or vehicle 24 h prior to measuring sucrose intake. During weeks 8-10, drug treatment was terminated while the CMS paradigm continued to test the durability of the antidepressant-like effect. A Mixed Model GEM with repeated measures was conducted on the data collected during weeks 3-10 (treatment duration and washout) from stressed animals, which revealed a significant main effect of Trial (F(7, 306.9) :=: 10.508, p < 0.0001), and a significant effect of Treatment (F(5, 70.2) = 8.31, p < 0.0001). Post-hoc testing with Sidak's multiple comparisons revealed that only the group treated with 0.75 mg / kg of base compound failed to differentiate from vehicle (F(l, 71.1) = 2.2499,p = 0.13) indicating a minimum efficacious dose of base compound of 1.5 mg / kg (i.p.). Rats exposed to CMS showed a robust anhedonic phenotype evidenced by a reduction in sucrose intake compared to control rats in weeks 1 and 2 of stress exposure; this reduction was maintained throughout the study in the vehicle group (Figure 26C). In the first week of base compound testing (week 3 of stress), administration of ketamine (10 mg / kg, i.p.) or base compound (3 or 9 mg / kg, i.p.) reversed the deficit in sucrose intake in stressed rats measured 24 h after dosing. The two highest doses of base compound (15 and 20 mg / kg, i.p.) caused substantial behavioral disruption in non-stressed animals, so animals from those two dose levels were re-randomized and assigned to receive either 0.75 or 1.5 mg / kg for the remainine trials. In weeks 4-7, ketamine and base compound (1.5-9 mg / kg) reversed the effects of CMS on sucrose intake while the lowest dose of base compound (0.75 mg / kg) was not effective. For weeks 8-10, stress continued but dosing ceased. The increase in sucrose intake caused by ketamine and base compound was maintained in weeks 8-9, largely returning to stressed vehicle levels by week 10, indicating that the anti-anhedonic effects of both compounds were durable through 15 days after the final dose. The rapid and durable effects of (rac)-ketamine in CMS appear to model the well-documented rapid acting efficacy of (rac)-ketamine in patients with depression. Figure 26D shows the percent time spent in the open arms in the Elevated Plus Maze (EPM), which was conducted 48 h after initial treatment. Open bars show data from unstressed control rats, while filled bars are rats exposed to CMS. A two-way ANOVA revealed a significant main effect of Treatment (F(5, 84) = 5.591, p = 0.0002), a significant main effect of Stress (F(l, 84) = 9.126, p == 0.0033) and a significant interaction (F(5, 84) == 2.568, p == 0.0327). Post-hoc testing with Sidak's multiple comparisons test revealed significant differences between stressed and unstressed groups treated with vehicle (p == 0.0040) and 0.75 mg / kg of base compound (p = 0.03 15) indicating these groups showed an increase in anxiety due to exposure to CMS. In rats dosed with base compound at >1.5 mg / kg (i.p.) or ketamine (10 mg / kg i.p.) anxietylevels were not different in control vs stressed rats indicating that drug treatment had reduced CMS-induced anxiety. Figure 26E shows the results from the Novel Object Recognition task (NOR). The NOR was conducted 72 h after the initial compound administration. Open bars show data from unstressed control rats, while filled bars are rats exposed to CMS. A two-way ANOVA revealed a significant main effect of Treatment (F(5, 84) = 2.988, / 7 == 0.0157), a significant main effect of Stress (F(l, 84) == 9.464, / ? = 0.0028) but no significant interaction (F(5, 84) = 1.834, p == 0.1150). In rats dosed with base compound at >1.5 mg / kg (i.p.) or ketamine (10 mg / kg, i.p.) recognition indices were not different in control vs stressed rats indicating that drug treatment had reduced CMS-induced impairment of recognition memory . Base compound was effective at reversing CMS-induced anhedonia, anxiety and cognitive impairment. At the minimal efficacious dose (MED) of base compound (1.5 mg / kg, i.p.) the peak plasma concentration was measured to be 92 ng / mL. In an additional experiment, the durability of a single administration of (raty-ketamine or base compound (1.5 or 9 mg / kg, i.p.), and the efficacy 24 h after a single oral administration of base compound (1, 3.2, 10 mg / kg, p.o.), were assessed. Figures 26F and 26G show the effects of (rac)-ketamine or base compound on sucrose intake in WKY rats (n=8 / group). Figure 26F shows the effect of a single administration of drug in week 3; sucrose intake was assessed 24 h later and then once weekly for a total of 3 weeks post-dose. A two-way ANOVA revealed a significant main effect, of group (F(4,35) = 12.34, p < 0.0001), time (F(2.456, 85.94) = 12,34, p < 0.0001), and a significant interaction (F(12, 105) = 4.334, p < 0.0001). Post hoc testing with Dunnett’s test showed that only stressed vehicle animals were significantly different from unstressed vehicle animals in week. 3 (p = 0.006) and week 4 (p = 0.0004). By week 5, all stressed animals were significantly different from unstressed vehicle animals Cp's < 0.001). The ability of a single dose of either base compound or (r«c)-ketamine to restore sucrose intake was maintained for 14 days, with sucrose intake returning to stressed baseline levels 21 days after dosing (Figure 26F). Figure 26G shows the effect of base compound (1-10 mg / kg, p.o.) administered orally, compared to (rac)-ketamine (10 mg / kg, i.p.) or base compound (1.5 mg / kg, i.p.) on sucrose intake 24 h later. A one-way ANOVA revealed a. significant, main effect of treatment (F(6. 49) = 10.58, < 0.0001). Asterisks indicate a significant difference from the vehicle + stress group using Dunnett’s post-hoc testing. When administered orally, base compound produced dosedependent. increases in sucrose intake, with 10 mg / kg restoring sucrose intake to unstressed levels 24 h after dosing (Figure 26G). At the oral MED of base compound (10 mg / kg), the peak plasma concentration was measured to be 257 ng / rnL. .As shown, in the first CMS, the base compound showed similar robust, rapid-acting, and durable antidepressant-like effects to ketamine. The base compound was effective at reversing the detrimental effects of stress on sucrose intake, anxiety, and memory' with once weekly dosing. The base compound is expected to also produce a rapid, robust antidepressant response in humans with intermittent, dosing. EXAMPLE 17 Studies of Motor Effects The effects of base compound (3.2-32 mg / kg, s.c.) on motor function were compared, to those of (rac)-ketamine (3.2-32 mg / kg, s.c.) in rats. Spontaneous locomotor activity (sLMA) was monitored for 30 min pre-dose and 60 min post-dose. Motor coordination was assessed 5 min after dosing using an accelerating rotarod. Plasma samples were collected from satellite rats to determine concentrations of base compound or draG-ketamine 30 or 18 min after dosing, respectively. Base compound (1-32 mg / kg, s.c.) was also assessed in mice in both sLMA and the rotarod. (a) Spontaneous Locomotor Activity (sLMA) The effects of base compound (3.2-32 mg / kg, s.c.) on sLMA in rats were compared to (rac)-ketamine (3.2-32 mg / kg, s.c.). Figure 27A top left depicts the spontaneous locomotor activity of rats (n==9 / group) dosed with vehicle, ketamine (3.2-32 mg / kg, s.c.) or base compound (3.2-32 mg / kg, s.c.; left) and in mice (n=10 / group) dosed with base compound (1-32 mg / kg, s.c.; right). Bar charts show total distance traveled over 0-30 min after dosing. Line graph of Figure 27A (top right) shows the time course of rat locomotor activity with data presented as 5 min bins, with rats dosed at time 0, and the given timepoint being the end of the 5 min bin (i.e., 5 rain === 05 mm). A one-way ANOVA revealed a significant main effect of treatment on the total distance traveled in the rats (F(6, 56)==== 20.13, p < 0.0001). Dunnett’s post-hoc test showed significant differences between vehicle and ketamine at 10 mg / kg ( / ; = 0.0001), and at 32 mg / kg (p < 0.0001), and between vehicle and base compound at 32 mg / kg (p < 0.0001). In mice there was no significant effect of base compound on spontaneous locomotor activity (F(4, 45) == 2.042, p === 0.1046) (Figure 27A (bottom). Both base compound and (rac)-ketamine produced dose-dependent effects on rat sLMA with (rac)-ketamine producing robust increases at doses >10 mg / kg, and base compound increasing activity only at 32 mg / kg (Figure 27 A; left). The exposure after base compound (32 mg / kg, s.c.) in satellite animals was 3,018 ng / mL, which was -30-fold higher than the exposure at the MED in CMS, indicating a large separation between efficacious plasma exposures and those associated with motor side effects (Figure 27A). (b) Rotarod The ataxic effects of base compound (3.2-32 mg / kg, s.c.) and (rac)-ketamine 3.2-32 mg / kg, s.c.) were explored in rats using the rotarod. Ketamine decreased the latency to fall off the rotarod at all doses tested, while base compound produced decreases only at 10 and 32 mg / kg (Figure 27B; left). The dose of base compound resulting in a 50% reduction in latency to fall (EDso) was 17.4 mg / kg, whereas for (rae)-ketamine it was 3.4 mg / kg. Ataxic effects were also assessed in mice. Like in rats, the base compound did not produce ataxia at 1 or 3.2 mg / kg and had only a minor effect on the latency to fall at 10 mg / kg (Figure 27B; right). The ED50 ataxic dose of base compound in mice -was 37.4 mg / kg, s.c.. In the locomotor and rotarod assays, rats were less affected after administration of base compound compared to ketamine. Importantly, the motor impairment, seen in these assays following base compound occurred at doses / exposures far higher than those that were efficacious in CMS. For base compound, 1.5 mg / kg (i.p.) was fully efficacious in CMS and no impairment in rotarod performance was seen at 3.2 mg / kg (s.c.), and only mild effects at 10 mg / kg (ED5o= 17.4 mg / kg, s.c.). Using plasma concentrations to compare across studies which used different routes of administration (ROA), the peak plasma concentration of base compound associated with the calculated ED50 for latency to fall off the rotarod was interpolated as 1,876 ng / mL. This is ~20-fold higher than the C!nax measured after administration of base compound at 1.5 mg / kg (i.p.; 92 ng / mL), the MED in CMS, indicating a large separation between antidepressant-like efficacy and motor side effects (Figure 27D). EXAMPLE 18 Conditioned Place Preference (CPP) The effects of base compound (1-32 mg / kg; s.c.) on CPP were compared to oxycodone (3 mg / kg; s.c.) in mice. Figure 27C shows the effects of base compound (1-32 mg / kg, s.c. ) compared to oxycodone (3 mg / kg, s.c.) on mouse conditioned place preference (n=10 / group). Graph shows the change in time spent on the drug paired side after place conditioning. While the one-way ANOVA revealed a significant main effect of treatment (F(5, 54) = 5.091, p = 0.0007), Dunnett’s post-hoc test showed that only the group treated with oxycodone was significantly different from vehicle (p = 0.0065). Base compound did not induce a CPP in mice at 1-32 mg / kg, s.c., while the animals treated with oxycodone (3 mg / kg, s.c.) as a positive control showed an increased time spent on the drug-paired side (Figure 27C). EXAMPLE 19 Rat EEG Studies The effects of base compound (1-10 mg / kg, s.c.) on EEG were measured using a within-subjects design in a cohort of 8 freely moving rats implanted with 2 cortical electrodes connected to a DSI transmitter as described in an article by Kantor et al., Behav. Brain Res. 2023: 449:114473, the contents related to the protocol incorporated by reference. Effects of base compound (1-10 mg / kg, s.c.) on the amplitude of cortical EEG oscillations were assessed for 30 min prior to and 180 min post-injection (Figure 28). Base compound produced a dose-dependent reduction in power in both theta (5-12 Hz) and beta (12-25 Hz) bands, while increasing power in the gamma (30-80 Hz) band (Figures 28A and 28C). These effects were not confounded by changes in activity levels (Figure 28B). The effect on gamma was most pronounced in the 10 mg / kg group and peaked between 50-70 Hz. The effects lasted -40 min in the 1 mg / kg group, -90 min in the 3.2 mg / kg group, and -120 min in the 10 mg / kg group (Figure 28A). Base compound had dose-dependent effects on delta (1-4 Hz; one-way ANOVA F(3, 31)= 1.03, p = 0.4), theta (5-12 Hz; one-way ANOVA F(3,31) = 4.63, p = 0.009, Tukey’s HSD test: Vehicle > 3.2 mg / kg and 10 mg / kg), beta (12-30 Hz, oneway ANOVA F(3, 31) = 3.59, p = 0.026, Tukey’s HSD test: Vehicle > 10 mg / kg) and gamma (30-80 Hz, one-way ANOVA F(3, 31) = 32.5, p <0.0001, Tukey’s HSD test: Vehicle < 3.2 mg / kg < 10 mg / kg; Figure 28D). The MED for decreasing theta and increasing gamma power was 3.2 mg / kg, which, based on subcutaneous rat PK, was associated with a peak plasma concentration of 342 ng / mL. The EEG is a quantitative translational biomarker of target engagement. Ketamine reduces power in low frequency bands and increases power in the gamma band both preciinically and clinically. The reduction of low' frequency activity and increase in gamma seen in the EEG experiment with base compound demonstrate clear target engagement, consistent with NMD AR blockade. A dose of 3.2 mg / kg (s.c.), winch achieves similar exposure to the minimum efficacious dose in CMS (1.5 mg / kg, i .p), was sufficient to affect this biomarker of NMD AR blockade, -which demonstrates this dose of base compound is producing significant engagement of NMD AR in vivo. Figure 27D provides an overview- of the plasma concentrations of base compound associated with the pharmacodynamic effects of the drug. Green lines represent the plasma concentration of base compound at the minimum efficacious doses in the chronic mild stress paradigm and forced swim test, as indicated. Red lines indicate the plasma concentrations associated with a 50% reduction in latency to fall off the rotarod or a significant increase in spontaneous locomotor activity, as indicated. The blue line represents the minimum plasma concentration of base compound associated with decreases in EEG theta power and increases in gamma power in rats. Based on these results, the data show that the base compound exhibits antidepressant activity in test animals predictive of the effect of the base compound in humans. C. Examples with Human Subjects in a Phase 2a Study EXAMPLE 20 / 1 Phase 2a Study in Patients with Major Depressive Disorder Study Design and Demographics. The following example describes a double-blind, placebo-controlled human study of base compound in patients with moderate to severe major depressive disorder (MDD) to evaluate the safety, pharmacokinetics, and pharmacodynamic and therapeutic effects of single and multiple oral doses of base compound ((J?)-2-(4-fluorophenyl)-2-(methylammo)cyclohexan-l-one). The study consisted of two parts, a crossover period comparing a single 140 mg dose of base compound to a single dose of placebo (Part A) and a repeat dose period examining the effects of 4 repeat doses of 140 mg or 210 mg base compound administered over two weeks, including a 4-week follow-up period after the last dose (Part B), In Part A, on Day 1 of the study, all patients (N = 46) were randomized to be administered either placebo or 140 mg base compound. Patients were then assessed through Day 14 for decreases in their depressive symptoms using the Montgomery-Asberg Depression Rating Scale-Structured Interview Guide for Montgomery-Asberg (MADRS-SIGMA) instrument. Two weeks following the initial dose (Day 15), all patients were crossed over to the treatment they had not previously received (140 mg base compound or placebo) and efficacy was evaluated with MADRS-SIGMA through Day 29, In Part B, patients received 4 repeat doses of base compound at either the 140 mg or 210 mg dose level on Day 29, 32, 36, and 39, and efficacy was measured at multiple time points using the MADRS-SIGMA during the dosing period and during a 28-day follow-up period (assessments on Day 30, 32, 36, 39, 40, 42 and 67, assessments on dosing days 32, 36, and 39 were conducted before drug administration on those days). The studv design is summarized in Figure 29. Patient demographics are summarized in Table 2 below. Patients were permitted to receive concomitant treatment with standard monoaminergic antidepressants provided they were stably dosed and the met enrollment criterion on the MADRS-SIGMA (score of >22). Approximately 40% of enrolled patients were receiving concomitant treatment with a selective serotonin reuptake inhibitor (SSRI). Table 2. Demographics of MDD Patients Randomized to Treatment with Base Compound Demographic Part A: PBO-> 140 nig, n=25 Part A: 140 mg -> PRO, 0=21 Age in years, mean 35.2 35.4 Sex, % female 48% 47.6% Race White, % 84% 95% Other, % 16% 5% BMI in kg / m2, mean 26.3 25.18 |      Day -1 MADRS Total Score, mean 32.1 32.5 Age at Onset of Depressive Symptoms, mean 18.6 19.35 Number of Prior Depressive Episodes, median 14.6 7.75 Concomitant Anxiety Disorder, % 25% 23.8% Pharmacokinetics. Pharmacokinetics observed in patients were consistent with those observed in healthy volunteers (see Examples 1 and 11). Efficacy. Base compound induced significantly greater reductions in MADRS scores than placebo in the first 14 days of Part A (Day 1 through Day 14). A between-subjects comparison during this period revealed a statistically significant difference between treatment with a single dose of base compound (140 mg) or placebo (PB) 1 day after (Day 2) drug administration (on Day 1), and a main effect of treatment over the first 14 days (Two-Way Anova, F(l,2I0) = 7.728, p = 0.0059). These results are shown in Figure 30. In Part B, repeat dosing with either 140 mg or 210 mg of base compound resulted in substantial further decreases in MADRS scores reiative to baseline and compared to a. single dose, and this effect was durable for at least 28 days following the last dose (Day 67 vs. Day 39). There was not a clear dose dependence for the effect of 140 mg versus 210 mg. These results are shown in Figure 31. CADSS. Using the same methods described in Example 3, CADSS scores were recorded pre-dose and at 0.5, 2, 4, and 8 h post-dose for each drug administration in Part A and Part B. The CADSS results for each drug administration in Part B are shown in Figure 32 by dose and time point. Consistent with the results in healthy volunteers (Figure 6), the percentage of subjects achieving a clinically significant dissociative state (CADSS > 4) was low at the 140 mg dose level. However, in contrast to the healthy volunteer studies, in the Phase 2a study, there was no appreciable increase in the incidence of dissociation at the 210 mg dose level compared to the 140 mg dose level, as quantified by CADSS. Accordingly, the 210 mg dose may also represent a minimally dissociative dose of base compound for use in the treatment of MDI). While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now7 occur to those of ordinary skill in the art. Therefore, it is to be understood that the appended claims are intended to cover all such modifications and changes as tall within the true spirit of the invention.

Claims

1,     A method of treating a patient having a psychiatric disorder comprising administeringorally to a patient in need thereof a base compound or a pharmaceutically acceptable salt thereof at a dose ranging from about 40 to about 360 mg relative to the base compound at each administration at treatment intervals ranging from every’ other week to three days a week during an acute induction phase of treatment, wherein the base compound is substantially pure (7?)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one.

2. The method according to claim 1 wherein base compound or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 40 to about 180 mg.

3. The method according to claim 1 wherein base compound or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 60 to about 140 mg.

4. The method according to any one of claims 1-3 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with an antidepressant.

5. The method according to any one of claims 1-4 wherein the antidepressant blocks the serotonin transporter.

6. The method according to claim 5 wherein the antidepressant is a selective serotonin reuptake inhibitor.

7. The method according to claim 6 wherein the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine.

8. The method according to claim 5 wherein the antidepressant drug is a serotoninnorepinephrine reuptake inhibitor.

9. The method according to claim 8 wherein the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

10. The method according to any one of claims 1 -9 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof orally in an amount ranging from, about 40 to about 180 mg relative to the base compound at each administration at treatment intervals ranging from weekly to every other week to the patient in need thereof during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

11. The method according to claim 10 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about 40 to about 140 mg.

12. The method according to any one of claims 1-9 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof in an amount ranging from about 20 to about 100 mg relative to the base compound at each administration at treatment interval s ranging from weekly to daily to the patient in need thereof during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

13. The method according to claim 12 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about 40 to about 80 mg.

14. The method according to any one of claims 10-13 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with an antidepressant during the maintenance phase.

15. The method according to claim 14 wherein the antidepressant is a selective serotonin reuptake inhibitor or a. serotonin-norepinephrine reuptake inhibitor.

16. The method according to any one of claims 10-15 wherein the maintenance treatment phase follows an induction treatment involving the administration of esketamine, arketamine, or racemic ketamine.

17. The method according to claim 16 wherein the esketamine, arketamine, or racemic ketamine is administered intravenously, intranasally, intramuscularly, subcutaneously, sublingually, or orally during the induction treatment.

18. The method according to claim 17 wherein esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously.

19. A method of treating a patient having a psychiatric disorder comprising administering to a patient in need thereof a base compound or a pharmaceutically acceptable salt thereof during an acute induction phase of treatment in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 hng / mL to about 3,600 hng / mL subsequent to each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax t anging from about 72 ng / mL to about 540 ng / mL subsequent to each administration at treatmentintervals ranging from every other week to three days a week, wherein the base compound is substantially pure (J?)-2-(4-fluorophenyl)-2-(methylamino)cyciohexan-1 -one.

20. The method according to claim 19 wherein base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h-ng / mL to about 2,100 h ng / mL or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL21. The method according to claim 19 wherein base compound or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 550 h ng / mL to about 1800 h-ng / mL or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 110 ng / mL to about 280 ng / mL.

22. The method according to any one of claims 19-21 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with an antidepressant.

23. The method according to claim 22 wherein the antidepressant blocks the serotonin transporter,24. The method according to claim 23 wherein the antidepressant is a selective serotonin reuptake inhibitor.

25. The method according to claim 24 wherein the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine.

26. The method according to claim 23 wherein the antidepressant drug is a serotoninnorepinephrine reuptake inhibitor.

27. The method according to claim 26 wherein the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

28. The method according to any one of claims 19-27 additionally comprising administering to the subject in need of treatment substantially pure base compound or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve in the plasma of the subject an ALIC ranging from about 390 h ng / mL to about 2,100 h-ng / mL subsequent to each administration or an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL subsequent to each administration at treatment intervals ranging fromweekly to every other week during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

29. The method according to claim 28 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the subject in need of treatment is an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 hng / mL to about 1,800 hng / mL or an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL during the maintenance treatment phase.

30. The method according to any one of claims 19-27 additionally comprising administering to the subject in need of treatment substantially pure base compound or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 230 h ng / mL to about 970 h ng / mL subsequent to each administration or an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / mL subsequent to each administration at treatment intervals ranging from weekly to daily during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

31. The method according to claim 30 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the subject in need of treatment is an amount sufficient to achieve in the plasma of the subject an AUC ranging from about 390 h-ng / mL to about 760 h-ng / mL or an amount sufficient to achieve in the plasma, of the subject a Cmax ranging from about 72 ng / mL to about 130 ng / mL during the maintenance treatment phase.

32. The method according to any one of claims 28-31 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with an antidepressant during the maintenance phase.

33. The method according to claim 32 wherein the antidepressant is a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.

34. The method according to any one of claims 28-33 wherein the maintenance treatment phase follows an induction treatment involving the administration of esketamine, arketamine, or racemic ketamine.

35. The method according to claim 34 wherein the esketamine, arketamine, or racemic ketamine is administered intravenously, intranasal ly, intramuscularly, subcutaneously, sublingually, or orally during the induction treatment.

36. The method according to claim 35 wherein esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously.

37. The method according to any one of claims 1-36 wherein the psychiatric disorder is major depressive disorder.38, The method according to any one of claims 1 -36 wherein the psychiatric disorder is treatment-resistant depression.

39. The method according to any one of claims 1-36 wherein the psychiatric disorder is a neuropsychiatric disorder.

40. The method according to any one of claims 1-36 wherein the psychiatric disorder is an anxiety disorder, bipolar depressive disorder, post-partum depression, obsessive-compulsive disorder, post-traumatic stress disorder, or a substance use disorder.

41. The method according to any one of claims 1-36 wherein the psychiatric disorder is an anxiety disorder selected from generalized anxiety disorder, panic disorder, and social anxiety disorder,42. The method according to any one of claims 1-36 wherein the psychiatric disorder is a substance use disorder selected from alcohol use disorder, opioid use disorder, amphetamine / methamphetamine use disorder, cocaine use disorder, tobacco / nicotine use disorder, and cannabinoid use disorder.

43. A. method of treating a patient having a psychiatric disorder comprising administering a base compound or a pharmaceutically acceptable salt thereof concurrently with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor to the patient in need thereof on a daily basis, wherein base compound or a pharmaceutically acceptable salt thereof is administered orally at a dose level ranging from about 20 to about 100 mg per dayrelative to the base compound, wherein the base compound is substantially pure (J?)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one.

44. The method according to claim 43 wherein the daily dose of base compound or a pharmaceutically acceptable salt thereof is administered as a single unit dose.

45. The method according to claim 43 wherein the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, vortioxetine, duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

46. The method according to claim 45 wherein fluoxetine is administered at a. daily dose ranging from about 10 to about 80 mg, paroxetine is administered at a daily dose ranging from about 10 to about. 60 mg, citalopram is administered at a daily dose ranging from about 10 to about 40 mg, escital opram is administered at a daily dose ranging from about 5 to about 20 mg, fluvoxamine is administered at a daily dose ranging from about 25 to about 300 mg, sertraline is administered at a daily dose ranging from about 50 to about 200 mg, vortioxetine is administered at a daily dose ranging from about 5 to about 20 mg, duloxetine is administered at a daily dose ranging from about 30 to about 120 mg, venlafaxine is administered at a daily dose ranging from about 37.5 to about 375 mg, desvenlafaxine is administered at a daily dose ranging from about 25 to about 200 mg, milnacipran is administered at a daily dose ranging from about 12.5 to about 200 mg, and levomilnacipran is administered at a daily dose ranging from about 20 to about 120 mg, wherein all dose levels are relative to the free base form.

47. The method according to any one of claims 43-46 wherein the daily dose of the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is administered as a single unit dose.

48. The method according to any one of claims 43-47 wherein the daily dose of base compound or a pharmaceutically acceptable salt thereof and the daily dose of the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor are administered together as a single unit dose in a single pharmaceutical composition.

49. The method according to any one of claims 43-48 wherein the psychiatric disorder is major depressive disorder.

50. The method according to any one of claims 43-48 wherein the psychiatric disorder is treatment-resi slant depress! on.

51. The method according to any one of claims 43-48 wherein the psychiatric disorder is a neuropsychiatric disorder.

52. The method according to any one of claims 43-48 wherein the psychiatric disorder is an anxiety disorder, bipolar depressive disorder, post-partum depression, obsessive-compulsive disorder, post-traumatic stress disorder, or a substance use disorder.

53. The method according to claim 52 wherein the psychiatric disorder is an anxiety disorder selected from generalized anxiety disorder, panic disorder, and social anxiety disorder.

54. The method according to claim 52 wherein the psychiatric disorder is a substance use disorder selected from alcohol use disorder, opioid use disorder, amphetamine / methamphetamine use disorder, cocaine use disorder, tobacco / nicotine use disorder, and cannabinoid use disorder.

55. The method according to any one of claims 1-54 wherein the mean weight of the patient ranges from about 65 kg to about 80 kg.

56. .4 method of treating a patient having pain comprising administering orally to the patientin need thereof a base compound or a pharmaceutically acceptable salt thereof during an acute induction phase of treatment at a dose ranging from about 40 to about 360 mg relative to the base compound at each administration at treatment intervals ranging from every' other week to three days a week, wherein the base compound is substantially pure (7?)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one.

57. The method according to claim 56 wherein base compound or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 40 to about 180 mg .

58. The method according to claim 56 wherein base compound or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 60 to about 140 mg.

59. The method according to any one of claims 56-58 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.

60. The method according to claim 59 wherein the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine.

61. The method according to claim 59 wherein the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

62. The1 method according to any one of claims 56-61 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof orally in an amount ranging from about 40 to about 180 mg relative to the base compound at each administration at treatment intervals ranging from weekly to every-' other week to the patient in need thereof during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

63. The method according to claim 62 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about 40 to about 140 mg.

64. The method according to any one of claims 56-61 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof orally in an amount ranging from about 20 to about 100 mg relative to the base compound at each administration at treatment intervals ranging from weekly to daily to the patient in need thereof during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

65. The method according to claim 64 wherein the dose level of base compound or a pharmaceutically acceptable salt thereof administered to the patient during the maintenance treatment phase ranges from about 40 to about 80 mg.

66. The method according to any one of claims 62-65 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with a selective serotonin reuptake inhibitor or a. serotonin-norepinephrine reuptake inhibitor during the maintenance phase.67, The method according to atty one of claims 62-66 wherein the maintenance treatment follows an induction treatment involving the administration of esketamine, arketamine, or racemic ketamine.

68. The method according to claim 67 wherein the esketamine, arketamine, or racemic ketamine is administered intravenously, intranasally, intramuscularly, subcutaneously, sublingually, or orally during the induction treatment.

69. The method according to claim 68 wherein esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously.

70. The method according to any one of claims 56-69 wherein the pain is chronic pain.

71. The method according to any one of claims 56-69 wherein the pain is neuropathic pain.

72. The method according to any one of claims 56-69 wherein the pain is chemotherapyinduced neuropathy.

73. The method according to any one of claims 56-72 wherein the treatment results in a decreased intake of opioids by the patient.

74. A method of treating a patient, having pain comprising administering a base compound or a pharmaceutically acceptable salt thereof concurrently with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor to a patient in need thereof orally on a daily basis, wherein base compound or a pharmaceutically acceptable salt thereof is administeredat a dose level ranging from about 20 to about 100 mg relative to the base compound per day, wherein the base compound is substantially pure (^)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one.

75. The method according to claim 74 wherein the daily dose of base compound or a pharmaceutically acceptable salt thereof is administered as a single unit dose.

76. The method according to claim 74 or 75 wherein the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, vortioxetine, duloxetine, venlafaxine, desveniafaxine, milnacipran, or levomilnacipran.

77. The method according to claim 76 wherein fluoxetine is administered at a daily dose ranging from about 10 to about 80 mg, paroxetine is administered at a daily dose ranging from about 10 to about 60 mg, citalopram is administered at a daily dose ranging from about 10 to about 40 mg, escitalopram is administered at a daily dose ranging from about 5 to about 20 mg, fluvoxamine is administered at a daily dose ranging from about 25 to about 300 mg, sertraline is administered at a daily dose ranging from about 50 to about 200 mg, vortioxetine is administered at a daily dose ranging from about 5 to about 20 mg, duloxetine is administered at a daily dose ranging from about 30 to about 120 mg, venlafaxine is administered at a daily dose ranging from about 37.5 to about 375 mg, desveniafaxine is administered at a daily dose ranging from about 25 to about 200 rag, milnacipran is administered at a daily dose ranging from about 12.5 to about 200 mg, and levomilnacipran is administered at a daily dose ranging from about 20 to about 120 mg, wherein all dose levels are relative to the free base form.

78. The method according to any one of claims 74-77 wherein the daily dose of the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor is administered as a single unit dose.

79. The method according to any one of claims 74-78 wherein the daily dose of base compound or a pharmaceutically acceptable salt thereof and the daily dose of the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor are administered together as a single unit dose in a. single pharmaceutical composition.

80. The method according to any one of claims 74-79 wherein the pain is chronic pain.

81. The method according to any one of claims 74-79 wherein the pain is neuropathic pain.

82. The method according to any one of claims 74-79 wherein the pain is chemotherapy induced neuropathy.

83. The method according to any one of claims 74-82 wherein the treatment results in a decreased intake of opioids by the patient.84, A dosing kit comprising unit doses of a first pharmaceutical composition comprising a base compound or a pharmaceutically acceptable salt thereof and a first pharmaceutical carrier therefor and unit doses of a second pharmaceutical composition comprising a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor and a second pharmaceutical carrier therefor and instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to a patient suffering from a psychiatric disorder or pain, wherein the base compound is substantially pure CR)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1 -one.

85. A pharmaceutical composition comprising a first component of about 20 to about 100 mg of a base compound or a pharmaceutically acceptable salt thereof relative to the base compound and a second component that is one of the following: about 10 to about 80 mg of fluoxetine, about 10 to about 60 mg of paroxetine, about 10 to about 40 mg of citalopram, about 5 to about 20 mg of escitalopram, about 25 to about 300 mg of fluvoxamine, about 50 to about 200 mg of sertraline, about 5 to about 20 mg of vortioxetine, about 30 to about 120 mg of duloxetine, about 37.5 to about 375 mg of venlafaxine, about 25 to about 200 mg of desvenlafaxine, about 12.5 to about 200 mg of milnacipran, or about 20 to about 120 mg of levomilnacipran, along with a pharmaceutical carrier therefor, wherein all dose levels are relative to the free base form, wherein the base compound is substantially pure (JR)-2-(4-fluorophenyl)"2-(methylamino)cyclohexan-l-one,86. The pharmaceutical composition of claim 85 wherein the first component is about 20 to about 100 mg of base compound or a pharmaceutically acceptable salt thereof and the second component is one of the follo wing: about 10 to about 80 mg of fluoxetine, about 10 to about 60 nig of paroxetine, about 10 to about 40 mg of citalopram, about 5 to about 20 mg of escitalopram, about 25 to about 300 mg of fluvoxamine, about 50 to about 200 mg of sertraline, or about 5 to about 20 mg of vortioxetine.

87. The pharmaceutical composition of claim 85 wherein the first component is about 20 to about 100 mg of base compound or a pharmaceutically acceptable salt thereof or apharmaceutically acceptable salt thereof and the second component is one of the following: about 30 to about 120 mg of duloxetine, about 37.5 to about 375 nig of venlafaxine, about 25 to about 200 mg of desvenlafaxine, about 12.5 to about 200 mg of milnacipran, or about 20 to about 120 mg of levomilnacipran.88, A method for treating a psychiatric disorder or pain in a subject comprising administering a base compound or a pharmaceutically acceptable salt thereof as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 13 to about 120 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 540 ng / mL subsequent to each administration at treatment intervals ranging from every other week to three days a week during an acute induction phase of treatment, wherein the base compound is substantially pure ( / ?)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-l-one.

89. The method according to claim 88 wherein the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 13 to about 60 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL.

90. The method according to claim 88 wherein the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 20 to about 47 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 110 ng / mL to about 280 ng / mL.

91. The method according to any one of claims 88-90 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 13 to about 60 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cm3x ranging from about 72 ng / mL to about 330 ng / mL subsequent to each administration at treatment intervals ranging from weekly to every other week during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

92. The method according to claim 91 wherein the base compound or a pharmaceutically acceptable salt thereof is administered to the patient during the maintenance treatment phase inan amount ranging from about 13 to about 47 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL.

93. The method according to any one of claims 88-90 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof as an IV bolus or short infusion in less than or equal to about 15 minutes in an amount ranging from about 7 to about 33 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / mL subsequent to each administration at treatment intervals ranging from weekly to daily during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

94. The method according to claim 93 wherein the base compound or a pharmaceutically acceptable salt thereof is administered to the patient during the maintenance treatment phase in an amount ranging from about 13 to about 27 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 130 ng / mL.

95. The method according to any one of claims 88-94 wherein base compound or a pharmaceutically acceptabl e salt thereof is administered concurrently with an antidepressant.

96. The method according to claim 95 wherein the antidepressant blocks the serotonin transporter.

97. The method according to claim 96 wherein the antidepressant is a selective serotonin reuptake inhibitor.

98. The method according to claim 97 wherein the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine.

99. The method according to claim 96 wherein the antidepressant drug is a serotoninnorepinephrine reuptake inhibitor.

100. The method according to claim 99 wherein the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

101. The method according to any one of claims 91-94 wherein the maintenance treatment follows an induction treatment involving the administration of esketamine, arketamine, or racemic ketamine.

102. The method according to claim 101 wherein the esketamine, arketamine, or racemic ketamine is administered intravenously, intranasally, intramuscularly, subcutaneously, sublingually, or orally during the induction treatment.

103. The method according to claim 102 wherein esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously.

104. The method according to any one of claims 88-103 wherein the disorder is major depressive disorder.

105. The method according to any one of claims 88-103 wherein the disorder is treatmentresistant depression.

106. The method according to any one of claims 88-103 wherein the disorder is a neuropsychiatric disorder.

107. The method according to any one of claims 88-103 wherein the disorder is an anxiety disorder, bipolar depressive disorder, post-partum depression, obsessive-compulsive disorder, post-traumatic stress disorder, or a substance use disorder.

108. The method according to any one of claims 88-103 wherein the disorder is an anxiety disorder selected from generalized anxiety disorder, panic disorder, and social anxiety disorder.

109. The method according to any one of claims 88-103 wherein the disorder is a substance use disorder selected from alcohol use disorder, opioid use disorder, amphetamine / methamphetanune use disorder, cocaine use disorder, tobacco / ni cotine use disorder, and cannabinoid use disorder.

110. The method according to any one of claims 88-103 wherein the disorder is chronic pain.

111. The method according to any one of claims 88-103 wherein the disorder is neuropathicpain.

112. The method according to any one of claims 88-103 wherein the disorder is chemotherapy induced neuropathy.

113. The method according to any one of claims 88-103 wherein the treatment results in a decreased intake of opioids by the patient.

114. A method for treating a psychiatric disorder or pain in a subject comprising administering a base compound or a pharmaceutically acceptable salt thereof as an IM injection in an amount ranging from about 20 to about 180 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72ng / mL to about 540 ng / mL subsequent to each administration at treatment intervals ranging from every other week to three days a week during an acute induction phase of treatment, wherein the base compound is substantially pure ( / ?)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-l-one.

115. The method according to claim 114 wherein the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 20 to about 90 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL.

116. The method according to claim 114 wherein the base compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 30 to about 70 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about. 110 ng / mL to about 280 ng / mL.

117. The method according to any one of claims 114-116 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof as an IM injection in an amount ranging from about 20 to about 90 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 330 ng / mL subsequent to each administration at treatment intervals ranging from weekly to every- other week during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

118. The method according to claim 117 wherein the base compound or a pharmaceutically acceptable salt thereof is administered to the patient during the maintenance treatment phase in an amount ranging from about 20 to about 70 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mL to about 280 ng / mL.

119. The method according to any one of claims 114-116 additionally comprising administering substantially pure base compound or a pharmaceutically acceptable salt thereof as an IM injection in an amount ranging from about 10 to about 50 mg relative to the base compound at each administration or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 39 ng / mL to about 150 ng / mL subsequent to each administration at treatment intervals ranging from weekly to daily during a maintenance treatment phase that commences immediately after the conclusion of the acute induction phase.

120. The method according to claim 119 wherein the base compound or a. pharmaceutically acceptable salt thereof is administered to the patient during the maintenance treatment phase in an amount ranging from about 20 to about 40 mg or in an amount sufficient to achieve in the plasma of the subject a Cmax ranging from about 72 ng / mLto about 130 ng / mL.

121. The method according to any one of claims 114-120 wherein base compound or a pharmaceutically acceptable salt thereof is administered concurrently with an antidepressant.

122. The method according to claim 121 wherein the antidepressant blocks the serotonin transporter.

123. The method according to claim 122 wherein the antidepressant is a selective serotonin reuptake inhibitor.

124. The method according to claim 123 wherein the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, or vortioxetine.

125. The method according to claim 122 wherein the antidepressant drug is a serotoninnorepinephrine reuptake inhibitor.

126. The method according to claim 125 wherein the serotonin-norepinephrine reuptake inhibitor is duloxetine, venlafaxine, desvenlafaxine, milnacipran, or levomilnacipran.

127. The method according to any one of claims 117-120 wherein the maintenance treatment follows an induction treatment involving the administration of esketamine, arketamine, or racemic ketamine.

128. The method according to claim 127 wherein the esketamine, arketamine, or racemic ketamine is administered intravenously, intranasally, intramuscularly, subcutaneously, sublingually, or orally during the induction treatment.

129. The method according to claim 128 wherein esketamine is administered intranasally, arketamine is administered subcutaneously, and racemic ketamine is administered intravenously.

130. The method according to any one of claims 114-129 wherein the disorder is major depressive disorder.

131. The method according to any one of claims 114-129 wherein the disorder is treatmentresistant depression.

132. The method according to any one of claims 114-129 wherein the disorder is a neuropsychiatric di sorder.

133. The method according to any one of claims 114-129 wherein the disorder is an anxiety disorder, bipolar depressive disorder, post-partum depression, obsessive-compulsive disorder, post-traumatic stress disorder, or a substance use disorder.

134. The method according to any one of claims 114-129 wherein the disorder is an anxiety disorder selected from generalized anxiety disorder, panic disorder, and social anxiety disorder, 135. The method according to any one of claims 114-129 wherein the disorder is a substance use disorder selected from alcohol use disorder, opioid use disorder, amphetamine / methamphetamine use disorder, cocaine use disorder, tobacco / nicotine use disorder, and cannabinoid use disorder.

136. The method according to any one of claims 114-129 wherein the disorder is chronic pain.

137. The method according to any one of claims 114-129 wherein the disorder is neuropathic pain.

138. The method according to any one of claims 114-129 wherein the disorder is chemotherapy induced neuropathy.

139. The method according to any one of claims 114-129 wherein the treatment results in a decreased intake of opioids by the patient,140. The method according to any one of claims 1-83 and 88-139 wherein the base compound is administered in the form of a pharmaceutical composition comprising the base compound and a pharmaceutically acceptable carrier.

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