Pharmaceutical preparations and methods for treating stimulant addiction and withdrawal

Abstract

Disclosed are pharmaceutical preparations comprising bromantane or an analogue of bromantane, and methods of using the preparations for pharmacotherapy to alleviate withdrawal syndrome and prevent relapse in the treatment of stimulant use disorder, to transition patients off medications that have dependence liabilities, or to facilitate extinction learning in the treatment of mental disorders.

Description

Attorney Docket No. 130948.00011PHARMACEUTICAL PREPARATIONS AND METHODS FOR TREATING STIMULANT ADDICTION AND WITHDRAWALRELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 763,839. filed Feb. 26, 2025, which is incorporated herein by reference in its entirety for all purposes.FIELD

[0002] Tire present disclosure relates to the field of medicine. Specifically, the disclosure involves the use of bromantane or its analogues to treat disorders of maladaptive learning.BACKGROUND

[0003] Central nervous system stimulants are known to be addictive. Tolerance to the effects of stimulants develops quickly and can lead to debilitating chronic dependence or overdose. Morbidity and mortality rates due to abuse of illicit stimulants (e.g., methamphetamine, cocaine) as well as misuse of licit stimulants (e.g., prescription amphetamine) have been increasing over the years, constituting a public health crisis.

[0004] Patients who are prescribed stimulant medications to treat neurological conditions under the supervision of a physician are also at risk of developing dependencies that can result in adverse effects which outweigh the benefits of treatment. For example, the current standard of care and first-line treatment for attention deficit disorders entails medication with either the benzylpiperazine -derived stimulant methylphenidate or phenethylamine-derived stimulant amphetamine. Patients taking these medications over a prolonged period of time tend to experience reduced efficacy, and discontinuing such prescriptions has been shown to worsen the original symptoms.

[0005] To date, no medication has been approved by the US Food and Drug Administration (FDA) for use in the treatment of Stimulant Use Disorder (StUD), colloquially referred to as stimulant addiction or dependence (e.g., amphetamine dependence, cocaine dependence). Behavioral and social interventions (e.g.. cognitive behavioral therapy, contingency management) are the primary methods utilized to treat StUD; however, the success rate of those psychological approaches is moderate. Pharmacological approaches to treatment have aimed to develop drugs that target specific neurotransmitter systems such as dopaminergic, serotonergic, GABAergic, glutamatergic, adrenergic, opioidergic, or muscarinic receptors; hormonal systems such asAttorney Docket No. 130948.00011cholecystokinin or ghrelin receptors; or metabolic pathways such as phosphodiesterases or hydroxysteroid dehydrogenase. Likewise, drugs with neuroprotective, anxiolytic, antidepressant, mood stabilizing, psychostimulant, antipsychotic, or immunotherapeutic properties have been investigated. However, a viable phannacotherapy that significantly impacts the pathology of stimulant dependence without adverse side effects has remained elusive.

[0006] StUD and other forms of dependence or addiction arc perpetuated, in part, by positive reinforcement, negative reinforcement, incentive salience, stimulus-response associations, and inhibitory control dysfunction. For example, the euphoric effects of a drug provide positive reinforcement, which increase the likelihood of repeated drug use and often drives drug-seeking behavior. Symptoms such as dysphoria or physical discomfort experienced during withdrawal from a drug are examples of negative reinforcement. In turn, psychophysiological associations are learned through these reinforcement mechanisms. Learned associations are not intrinsically adverse, but those that manifest as cravings, habits, or impulsivity can be detrimental. In the context of mental disorders such as StUD, incentive salience ("cravings'), stimulus-response associations (‘habits’), and inhibitory control dysfunction (‘impulsivity') are indicative of maladaptive learned associations that result in subconscious motivational states which shift attention toward counterproductive thoughts or activities, such as drug use.

[0007] Approaches that rely on animal models to identify potential pharmacotherapies for StUD have not been successful because the translational disconnects between animal models of StUD and clinical efficacy cannot be fully bridged. Animal models designed to measure aspects of drug dependence such as selfadministration, conditioned place preference, reinstatement, drug discrimination, and withdrawal generally achieve face validity , but their predictive validity is limited to certain paradigms. For example, selfadministration of stimulants (e.g., cocaine, amphetamine) in rodents does not fully capture the complexity of human drug use because animals do not experience the same socio -environmental influences and decisionmaking processes that are involved in human StUD. In animals, drug-seeking behavior is often driven by direct reinforcement mechanisms rather than social, emotional, and cognitive factors that influence human drug use. Humans consume stimulants for a myriad of reasons that are not replicable in animal models, including socialization and performance enhancement. Furthermore, StUD in humans is often accompanied by psychiatric comorbidities such as anxiety, depression, and personality disorders. Animal models do not fully replicate these psychiatric states, which can significantly impact the pathology of StUD and efficacy of pharmacotherapies .

[0008] Mental disorders characterized by the fonnation of inappropriate or dysfunctional associations between stimuli and responses in humans can be classified as disorders of maladaptive learning, a distinctAttorney Docket No. 130948.00011subset of canonically defined mental disorders. These disorders arise when normal learning processes become distorted, leading to behaviors that are harmful, excessive, or persist despite negative consequences. While traditionally categorized under broader psychiatric conditions such as depression, anxiety disorders, stress-related disorders, a subset of these conditions is driven specifically by maladaptive learning mechanisms. In such cases, pathological behaviors are reinforced and persist independently of their original external triggers. StUD is one such example, as persistent drug -seeking behaviors are maintained despite the absence of external reinforcement. Similarly, a maladaptive learning -driven subset of depression may arise when dysfunctional associative processes reinforce negative drought patterns, making these cases resistant to conventional antidepressants. Because these maladaptive learning subtypes have distinct underlying mechanisms, they may exhibit differential responsiveness to pharmacotherapy, where standard treatments may fail to address the core associative dysfunction.

[0009] Maladaptive learning is particularly challenging to rectify because learned responses tend to persist even after external reinforcement and triggers are eliminated. In other words, relapse potential (aka relapse vulnerability) remains high until the imprinted response is sufficiently unlearned. Extinction of maladaptive responses is the basis for extinction learning in the treatment of mental disorders that arise from maladaptive learning. While pharmacotherapies such as cycloserine, selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline), and propranolol have been proposed to influence extinction learning processes during exposure therapy sessions, drey do not directly modulate maladaptive stimulus-response associations, making them ineffective at disrupting strongly imprinted maladaptive behaviors. Furthermore, their lack of engagement with motivational and reward systems further limits their ability to produce lasting behavioral change and reduces their clinical utility. In contrast, the pharmacotherapy disclosed herein addresses these limitations and reduces the need for intensive psychotherapy, providing a targeted pharmacological approach to the treatment of disorders characterized by maladaptive learning.

[0010] Bromantane is an atypical psychostimulant that was originally investigated for its immunomodulatory, stimulant, and adaptogenic properties in the 1980’s at the Research Institute of Pharmacology in Moscow, USSR. Bromantane has the capacity to boost physical endurance and was detected in Olympic athletes prior to the 1996 games, leading to its ban as a performance-enhancing drug by the World Anti-Doping Agency in 1997. Several safety and efficacy studies were conducted in Russia from 1993-2015 that demonstrated bromantanc’s antiasthenic properties. Oral tablets containing bromantane were approved forthe treatment of neurasthenia around 2009 (Russian State Register of Medicines: LSR-010257 / 08).Bromantane has also been studied by various investigators around the world for use in the treatment of fibrotic diseases, cancer, liver disease, inflammation, and Parkinson's disease.Attorney Docket No. 130948.00011

[0011] Classified as an actoprotector, bromantane is known to enhance the body's resistance to physical stress. Its pharmacology is complex, and the complete mechanism of action is still under debate in the scientific community. Its biological activity involves immunomodulation and modulation of several neurochemical processes. Bromantane is thought to produce its stimulant effects by increasing production of L-DOPA and dopamine in the hypothalamus, hippocampus, and striatum through de novo activation of tyrosine hydroxylase. Paradoxically, it also produces anxiolytic effects by inhibiting the expression of the GABA transporter gene (Gat3), enhancing GABAergic transmission by increasing GABA availability in synaptic gaps. Furthermore, it has been shown to promote neuronal survival and plasticity by causing an increase in the synthesis of effector kinases in the mitogen-activated protein kinase cascade (ERK1 / ERK2) and upregulation of neurotrophic factors like brain -derived neurotrophic factor (BDNF) and nerve growth factor (NGF). The host of biological activities exhibited by bromantane is unprecedented for a single-agent pharmacotherapy in the treatment of drag dependence.SUMMARY

[0012] Conventional pharmacotherapeutic approaches to StUD often rely on multiple active agents to address withdrawal symptoms, relapse vulnerability, and comorbid conditions, leading to cascading indications, where each additional medication contributes to polypharmacy, increased side effects, and treatment complexity. While bromantane has been previously studied for other indications, it was not recognized as a stand-alone pharmacotherapy capable of addressing these interconnected challenges. Its effectiveness in this context, without the use of adjunctive medications, was neither anticipated nor suggested by prior therapeutic applications. The ability of bromantane to function as a comprehensive, single -agent intervention represents an unexpected advancement over conventional multi-drug treatment regimens and offers a novel approach to mitigating the risks associated with polypharmacy in drug dependence treatment.

[0013] Disclosed is the surprising discovery that the mild stimulant and anxiolytic drug bromantane has the potential to eliminate or substantially reduce cravings and withdrawal syndrome associated with dependence to known stimulants of abuse, including but not limited to amphetamine, methamphetamine, and cocaine, attention-deficit / hyperactivity disorder (ADHD) medications without leading to secondary dependence. Furthermore, bromantane was found to simultaneously alleviate comorbidities that either arise from or exacerbate drug dependency, notably by reversing maladaptive conditioned responses. The corrective effect on the pathology of drug dependence and underlying mental disorders is rapid and remains durable after discontinuation of bromantane. Therefore, bromantane has utility as a single-agent, short-regimen, therapeutic to facilitate extinction learning in the treatment of StUD or other disorders of maladaptive learning. In anAttorney Docket No. 130948.00011embodiment, single-agent refers to a therapeutic agent that does not need a second therapeutic agent to be administered.

[0014] Dopaminergic activity in the brain has been implicated in the neurobiological changes that are associated with drug dependence. However, bromantane’s ability to modulate dopamine does not fully account for its effects on the pathology of StUD. Clinical studies of other drugs with varying degrees of specificity and selectivity to modulate dopamine in the brain have not been successful as monotherapies in the treatment of StUD. The non-selective mechanism of action of bromantane is serendipitously harmonious in terms of the broad spectrum of advantageous phannacological effects it produces to enable extinction learning. This is an emergent property that is not predictable from what is known about the mechanism of action of bromantane or from other information available about bromantane. Therefore, the use of bromantane to facilitate extinction learning in the treatment of drug dependence or other mental disorders is not obvious.

[0015] To investigate the utility of bromantane as a single-agent pharmacological intervention to interrupt stimulant dependence, an exploratory study was conducted with participants who had self-reported drug dependencies to a drug of concern. The intervention consisted of Test Article (bromantane) administered at a dose of 50 mg qtiaque die (qd, i.e., once daily) per osis (po, i.e., by mouth) for 7 days, starting on the first day of Week 1 of the study. Results from the exploratory study are summarized in [FIG. 2], The number of days the drug of concern was used by the participant during each 1 -week period during the 4-week study is shown in the Drug Dependency column. Symptom severities of comorbid conditions shown in the Comorbidity column were self-reported by each participant at the end of each week of the study using 5 -point Likert rating scale where 5 = symptom severity similar to severity pre-intervention, 4 = slight improvement compared to pre-intervention severity, 3 = significantly diminished symptoms, 2 = mild symptoms, 1 = no symptoms. Participants with cocaine or amphetamine dependencies achieved abstinence on the first day of intervention with the Test Article and were able to maintain abstinence for approximately three weeks. The participant with opioid dependence reported a reduction in opioid use during the period of intervention with the Test Article due to reduced ‘cravings.’ Participants also reported an unplanned reduction in caffeine use.

[0016] In addition to demonstrating utility as a single-agent pharmacological intervention to interrupt stimulant dependence, it was discovered that bromantane has utility as a treatment for certain comorbidities that are specifically underpinned by maladaptive learning, such as occupational burnout exacerbated by conditioned fear responses and attention-deficit / hyperactivity disorder arising from inhibitory control dysfunction. Furthermore, participants in the exploratory study reported improved temperaments, citing a higher threshold for irritability or anger. Alleviation of insomnia caused by rumination was also noted.Analysis of tire subjective effects reported by the participants revealed a pronounced reduction inAttorney Docket No. 130948.00011counterproductive behaviors and thought patterns triggered by conditioned stimuli. This mode of action suggests that bromantane induces extinction of maladaptive stimulus-response associations, a process which can be utilized to treat certain forms of dependence as well as other mental disorders characterized by maladaptive conditioned responses or relapse vulnerability. Therefore, the present disclosure also provides novel therapeutic methods of use for bromantane to facilitate extinction learning in the treatment of mental disorders or syndromes.

[0017] Based on the observations disclosed herein for bromantane, it is anticipated that structural or functional analogues of bromantane may act similarly to induce extinction of maladaptive stimulus-response associations in humans. Therefore, the present disclosure also provides novel therapeutic methods of use for analogues of bromantane. Disclosed herein are compositions and methods of administering a therapeutically effective amount of a pharmaceutical preparation of bromantane, or an analogue thereof, to eliminate or substantially reduce cravings and withdrawal syndrome associated with dependence to known stimulants of abuse, including but not limited to amphetamine, methamphetamine, and cocaine, attention-deficit / hyperactivity disorder (ADHD) medications without leading to secondary dependence. Further, disclosed herein are compositions and methods of administering a therapeutically effective amount of a pharmaceutical preparation of bromantane, an analogue thereof, for treating Stimulant Use Disorder (StUD), colloquially referred to as stimulant addiction or dependence (e.g., amphetamine dependence (e.g., methamphetamine dependence), cocaine dependence).

[0018] The objective of the present disclosure is to improve the standard of care for certain mental disorders characterized by maladaptive learning, such as StUD, by facilitating extinction learning through the administration of a therapeutically effective amount of bromantane or an analogue thereof. While bromantane or an analogue of bromantane can be administered uncompounded, administering a pharmaceutical preparation that ensures consistent absorption and fosters patient adherence to the treatment regimen is advantageous. For example, the onset of therapeutic effect for orally administered crystalline bromantane free base is slow (2-3 hours) due to solubility-limited absorption and high first-pass extraction. Preparations that improve bromantane ’s solubility or bioavailability to produce a faster onset of therapeutic effect are advantageous for addressing acute incentive salience expeditiously in the treatment of StUD, thereby increasing the likelihood of patient adherence to the treatment regimen and reducing the likelihood of relapse. Accordingly, the present disclosure also provides novel, advantageous pharmaceutical preparations of bromantane and their methods of use.

[0019] In an embodiment, presented herein, is a method of treating a disorder of maladaptive learning, the method comprising (a) assessing a subject in need thereof suffering from symptoms of a mental disorder orAttorney Docket No. 130948.00011syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; and (b) facilitating extinction learning in the subject in need thereof by administering a therapeutically effective amount of a pharmaceutical preparation of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

[0020] In an embodiment, presented herein, is a method of treating stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof.

[0021] In an embodiment, presented herein, is a method of treating a disorder of maladaptive learning, the method comprising (a) assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; and (b) facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Ri, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, Rs, and Re, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane);L is independently selected from amine, amide, or imine; andthe chemical structure differs in at least one substituent (Ri, R2, R3, R4, Rs, Re, or L) such that it is structurally distinct from bromantane.Attorney Docket No. 130948.00011

[0022] In an embodiment, presented herein, is a method of treating a disorder of maladaptive learning, the method comprising facilitating extinction learning in the subject in need thereof by administering to tire subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Ri, R2, and Rs are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, Rs, and Re, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazolc, isothiazolc, pyrazolc, triazoic, tctrazolc, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane);L is independently selected from amine, amide, or imine; andthe chemical structure differs in at least one substituent (Ri, R2, Rs, R4, Rs, Re, or L) such that it is structurally distinct from bromantane.

[0023] In an embodiment, presented herein, is a method of modulating a network of receptors, the method comprising facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, wherein the receptors are selected from cannabinoid receptor 2 (CB2), androgen receptor (AR), amylin receptor subtype 3 (AMY3), orexin receptor 2 (0X2), or combinations thereof.

[0024] In an embodiment, presented herein, is a pharmaceutical preparation comprising a therapeutically effective amount of bromantane as a drug substance in the form of a salt, solvate, complex, or conjugate; and one or more pharmaceutically acceptable excipients that function to inhibit crystallization, wherein, the morphology of the drug substance is amorphous.Attorney Docket No. 130948.00011

[0025] In an embodiment, presented herein, is a pharmaceutical preparation comprising a therapeutically effective amount of bromantane in amorphous free base form; and one or more pharmaceutically acceptable excipients.

[0026] In an embodiment, presented herein, is a method of treating a comorbidity associated with stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, or an analogue of bromantane, or a pharmacally acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 illustrates the chemical structure of bromantane.

[0028] FIG. 2 is a table showing the results from an exploratory study that tracked the effects of pharmacological intervention with bromantane on participants' frequency of drug use and symptoms of comorbid conditions.

[0029] FIG. 3 is a graph showing the 'H NMR spectrum of bromantane free base in DMSO-d6.

[0030] FIG. 4 is a series of PLM images showing the birefringence of bromantane free base Form I, bromantane hydrochloride salt Form I, bromantane maleate salt Form I, bromantane oxalate salt Form I, bromantane sulfate salt Fonn I, and bromantane methanesulfonate salt Fomi I.

[0031] FIG. 5 is a graph showing a differential scanning calorimetry (DSC) thermogram of bromantane free base Form I.

[0032] FIG. 6 is a graph showing the PXRD patterns of bromantane oxalate salt Form I, bromantane maleate salt Form I, bromantane methanesulfonate salt Form I, bromantane sulfate salt Form I, bromantane hydrochloride salt Form I, and bromantane free base Form I.

[0033] FIG. 7 is a table illustrating the general chemical structure of Formula I, the substituent pattern that constitutes bromantane, and the various substituent substitution permutations that represent analogues of bromantane.

[0034] FIG. 8 is a tabic showing the results from a bromantane salt screening study.

[0035] FIG. 9 is a graph showing the1H NMR spectrum of bromantane hydrochloride salt in DMSO-d6.Attorney Docket No. 130948.00011

[0036] FIG. 10 is a graph showing the 'H NMR spectrum of bromantane hydrochloride salt in CDCI3.

[0037] FIG. 11 is a graph showing the13C NMR spectrum of bromantane hydrochloride salt in CDCI3.

[0038] FIG. 12 is a graph showing the DSC thermogram of bromantane hydrochloride salt Form I.

[0039] FIG. 13 is a graph showing the 'H NMR spectrum of bromantane maleate salt in DMSO-d6.

[0040] FIG. 14 is a graph showing the DSC and thermogravimetric analysis (TGA) thermograms of bromantane maleate salt Form I.

[0041] FIG. 15 is a graph showing the 'H NMR spectrum of bromantane oxalate salt in DMSO-d6.

[0042] FIG. 16 is a graph showing the DSC and TGA thermograms of bromantane oxalate salt Fonn I.

[0043] FIG. 17 is a graph showing the 'H NMR spectrum of bromantane sulfate salt in DMSO-d6.

[0044] FIG. 18 is a graph showing the DSC and TGA thermograms of bromantane sulfate salt Form I.

[0045] FIG. 19 is a graph showing the DSC thermogram of bromantane methanesulfonate salt Fonn I.

[0046] FIG. 20 is a graph showing the PXRD patterns of four distinct crystalline polymorphs of the bromantane phosphate salt.

[0047] FIG. 21 is a graph showing the PXRD patterns of two distinct crystalline polymorphs of the bromantane p-tosylate salt and two distinct cry stalline polymorphs of the bromantane ethanedisulfonate salt.

[0048] FIG. 22 is a graph showing the isothermal water sorption and desorption behaviors of bromantane free base Form I.

[0049] FIG. 23 is a graph showing the isothermal water sorption and desorption behaviors of bromantane hydrochloride salt Form I.

[0050] FIG. 24 is a table showing the aqueous equilibrium solubilities measured for bromantane free base Form I, bromantane maleate salt Form I, bromantane oxalate salt Form I, and bromantane sulfate salt Form I.

[0051] FIG. 25 is a table showing the equilibrium solubility of bromantane free base Form I in organic solvents.Attorney Docket No. 130948.00011

[0052] FIG. 26 is a graph showing the PXRD patterns of bromantane free base ASD in copovidone, bromantane free base OTF dosage form, and bromantane carboxymethyl-|3-cyclodextrin inclusion complex.

[0053] FIG. 27 is a graph showing the results of a dissolution experiment comparing the kinetic solubility profdes of various pharmaceutical preparations of bromantanes.

[0054] FIG. 28 is a Venn diagram illustrating the phenotypic overlap among disorders of maladaptive learning, canonical mental disorders, and syndromes. As shown, disorders of maladaptive learning include maladaptive learning phenotypes present in subjects with a canonical mental disorder, in subjects with a syndrome, and in subjects with neither a syndrome nor a canonical mental disorder diagnosis. The intersections indicate that a disorder of maladaptive learning may overlap with, be comorbid with, or contribute to a canonical mental disorder and or a syndrome, while also including transdiagnostic or subclinical maladaptive learning phenotypes not captured by canonical diagnostic classifications.

[0055] FIG. 29 is a graph showing a lipid bilayer GFA assay result for bromantane and concentration dependent effects on NormRate.

[0056] FIG. 30 is a graph showing a lipid bilayer GFA assay result for bromantane and concentration dependent effects on bilayer deformation energies.

[0057] FIG. 31 is a graph showing a lipid bilayer GFA assay result for bromantane and concentration dependent effects on free energy shift.

[0058] FIG. 32 is a graph showing a cell based arrestin functional assay for human CB2 receptor agonism.

[0059] FIG. 33 is a graph showing a cell based cAMP functional assay for human CB2 receptor agonism.

[0060] FIG. 34 is a graph showing a cell based NHR translocation functional assay for human AR receptor antagonism.

[0061] FIG. 35 is a graph showing a cell based cAMP TR-FRET functional assay for human AMY3 receptor agonism.

[0062] FIG. 36 is a graph showing a cell based Ca flux functional assay for human OX2 receptor antagonism.Attorney Docket No. 130948.00011DETAILED DESCRIPTIONDefinitions

[0063] A. an, and the: Singular articles a, an, and the are used in the text for readability, but should be understood to include plural referents unless the context clearly dictates otherwise.

[0064] Addiction: As used herein, the terms addiction and dependence are used synonymously and refer to a condition in which a substance, behavior, thought pattern, or emotional state is persistently reinforced, leading to continued engagement despite potential adverse consequences. This includes both physical and psychological aspects, such as physiological withdrawal, craving, habitual reinforcement, or sustained reliance, even in the absence of compulsive seeking behavior. The term applies broadly to substance -related conditions as well as maladaptive patterns of cognition, behavior, or affective states, including excessive engagement with electronic devices, gambling, emotional fixation, or reliance on prescribed phannacotherapies, regardless of whether withdrawal symptoms or compulsive use are present.

[0065] Administer: As used herein, the term administer refers to the act of delivering a drug into the body of a subject by one or more delivery routes. For example, when the subject swallows a dose of the drug in the fomr of a tablet, the dose can be said to have been administered orally. Nonlimiting examples of delivery¬ routes include oral, sublingual, buccal, intranasal, transdennal, or subcutaneous. Nonlimiting examples of drugs include therapeutic agents, substances of abuse (licit or illicit drug), dietary supplements, herbal remedies, or any other substances intended to affect the structure or function of the body. It is to be understood that administration of the drug can be carried out either by the subject themselves (selfadministration) or by another person, such as a healthcare professional or caregiver.

[0066] Avoidance behaviors: As used herein, the term avoidance behavior refers to an action taken to evade, escape, or reduce exposure to a perceived threat, discomfort, or distressing situation. Avoidance behaviors are learned and reinforced overtime, often leading to long-term maladaptive patterns that can compound distress. A subject exhibiting avoidance behavior may go to great lengths to avoid triggers, such as skipping work to avoid stress, which can result in worsening anxiety and decreased overall functioning. Avoidance behaviors are typically negatively reinforced, meaning that the removal of a negative or distressing stimulus (e.g., anxiety, fear) strengthens the behavior. In one example, the subject exhibiting avoidance behavior may avoid a social event to reduce immediate anxiety, thereby alleviating the anxiety but reinforcing the avoidance behavior. In another example, the subject exhibiting avoidance behavior may consistently avoid public speaking, thereby negatively reinforcing the association between public speaking and anxiety,Attorney Docket No. 130948.00011counterproductively causing the association with anxiety to become more intense and persistent over time. This negative reinforcement perpetuates maladaptive learning by making avoidance a default coping strategy.

[0067] Behavioral rigidity: As used herein, the term behavioral rigidity refers to the inflexible adherence to specific behaviors or routines, despite changing circumstances or the absence of a logical basis for such persistence. A subject exhibiting behavioral rigidity may struggle to alter their responses based on feedback or new information and may become distressed when deviations from routines or habits occur.

[0068] Canonical mental disorders: As used herein, the term canonical mental disorders refers to mental disorders defined and classified within widely accepted clinical diagnostic frameworks, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), together with recognized subtypes, specifiers, and diagnostic equivalents thereof, as such frameworks may be revised from time to time. Hie term is used for reference to established diagnostic taxonomies and does not limit the scope of disorders of maladaptive learning described herein. Unless the context clearly indicates otherwise, references herein to “mental disorders” are intended to refer to canonical mental disorders as defined in this paragraph. Disorders of maladaptive learning as described herein are defined based on maladaptive reinforcement, conditioned responding, or persistence of maladaptive associations, and therefore may be transdiagnostic and may overlap with, or be distinct from, canonical mental disorders, [FIG. 28] .

[0069] Cognitive distortions: As used herein, the term cognitive distortion refers to an irrational, biased, or exaggerated thought pattern that can reinforce negative emotions or behaviors. A subject experiencing cognitive distortion has a skewed perception of reality that can lead to maladaptive responses to everyday situations. Common examples include catastrophizing, overgeneralization, and personalization. In one example, the subject experiencing cognitive distortion may catastrophize (expect the worst possible outcome) social interactions, leading to avoidance of social situations and thereby reinforce social anxiety and maladaptive avoidance behaviors. In another example, the subject experiencing cognitive distortion may overgeneralize (believe that if something happens once, it will always happen) a positive experience, such as euphoria under the influence of a drug, and come to believe that using the drug will always lead to pleasurable experiences. This belief thereby reinforces drug-seeking behavior despite diminishing positive outcomes and the potential for harmful consequences. In another example, the subject experiencing cognitive distortion may personalize (misattribute causation to oneself) negative events, such as the death of a loved one, believing their actions directly caused the loss. This guilt may lead the subject to adopt maladaptive behaviors, such as withdrawing from social support or engaging in self-punishing activities, thereby reinforcing a pattern of selfblame. Cognitive distortions can also interfere with adaptive learning by preventing subjects from accuratelyAttorney Docket No. 130948.00011processing information from their experiences, thereby hindering the development of effective coping strategies.

[0070] Complex dosing regimen: As used herein, the term complex dosing regimen refers to a non-fixed dosing regimen in which the amount of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, the dosing interval, the duration of dosing, or any combination thereof is intentionally varied over time within a course of treatment to achieve, maintain, or optimize a therapeutic response in a subject. A complex dosing regimen may comprise two or more phases, including, without limitation, an induction phase, a maintenance phase, a discontinuation phase, or any combination thereof. Nonlimiting examples of a complex dosing regimen include stepwise dose reduction, stepwise dose escalation, interval extension, interval shortening, intermittent dosing, pulse dosing, loading-dose followed by maintenance dosing, tapering schedules, and regimens that transition from daily dosing to less frequent dosing. A complex dosing regimen is distinguished from a fixed dosing regimen in which substantially the same dose amount is administered at substantially the same dosing interval throughout the treatment period.

[0071] Compulsive behaviors: As used herein, the term compulsive behavior refers to a repetitive action performed to reduce or prevent distress (e.g., anxiety, sorrow, discomfort), even when the action is excessive or not logically connected to the distress. Compulsive behavior is negatively reinforced because the urge to perform the action is driven by short-term relief from distress. This negative reinforcement strengthens the behavior, making it more likely to be repeated in similar situations, thus contributing to maladaptive learning. Compulsive behaviors can generalize to other areas of life. For example, a subject who develops a compulsion related to cleanliness might start applying similar compulsive behaviors to other areas, such as checking locks or counting objects, leading to a more pervasive pattern of maladaptive behavior. Compulsive behaviors often result in long-term negative consequences, such as increased anxiety, social isolation, or impaired functioning. Recognizing compulsive behaviors involves noting actions that the subject perfonns with a sense of urgency or to relieve distress, such as repeated handwashing to reduce contamination fears, even when it interferes with normal life activities.

[0072] Conditioned fear responses: As used herein, the temi conditioned fear response refers to an automatic response of fear or anxiety that occurs when a subject learns to associate a neutral stimulus with a fearful or traumatic event. In maladaptive learning, conditioned fear responses become ingrained and can be triggered by stimuli that pose no actual threat. The subject exhibiting conditioned fear responses may have phobic reactions or panic attacks in response to certain stimuli. For example, a subject with posttraumatic stress disorder who experienced a traumatic event in a war zone may develop a conditioned fear response to loud noises, such as fireworks, which trigger intense fear and panic attacks despite being in a safe environment.Attorney Docket No. 130948.00011

[0073] Coping mechanisms: The terms coping mechanism, coping strategy, and coping technique are used interchangeably herein. As used herein, the term coping mechanism refers to a cognitive approach or behavioral response, whether conscious or subconscious, that a subject employs to manage stress, emotions, or difficult situations with the aim of maintaining psychological well-being. Adaptive coping mechanisms can become engrained through repeated use and reflection, thereby contributing to adaptive learning - a process by which the subject acquires or modifies behaviors, skills, or thought patterns that result in flexible, beneficial, and appropriate responses to various situations. Maladaptive coping mechanisms can become similarly engrained by providing short-term relief from stress, emotions, or difficult situations. However, maladaptive coping mechanisms do not result in flexible, beneficial, and appropriate responses in certain situations and may lead to negative outcomes, exacerbating long-term distress. A subject with maladaptive coping mechanisms may resort to self-destructive behaviors to manage stress, emotions, or difficult situations, resulting in a cycle of increased distress and dysfunction. Nonlimiting examples of maladaptive coping mechanisms include substance abuse, excessive avoidance behaviors, and self-harm.

[0074] Disorder of maladaptive learning: As used herein, the term disorder of maladaptive learning refers to a condition in which a subject exhibits specific deficits in learning processes, such as difficulties in extinction learning and persistent maladaptive responses to certain stimuli. Unlike the general concept of maladaptive learning, which encompasses the acquisition or reinforcement of harmful behaviors, thoughts, or emotional responses, a disorder of maladaptive learning is characterized by a subject's chronic inability to unlearn these harmful patterns and adapt to new, healthier ones. Canonical mental disorders or syndromes that are stereotypically associated with maladaptive behaviors or thought patterns do not necessarily constitute a disorder of maladaptive learning, and a disorder of maladaptive learning does not necessarily align with these canonical mental disorders or syndromes, [FIG. 28], Treatment of a disorder of maladaptive learning benefits from targeted interventions aimed at extinguishing the subject's maladaptive responses. In some instances, beneficial responses can be introduced and reinforced through targeted re-learning processes, effectively replacing the maladaptive responses with healthier, adaptive ones.

[0075] Emotional dysregulation: As used herein, the term emotional dysregulation refers to the inability to manage emotional experiences in a healthy, adaptive way. Emotional dysregulation encompasses overly intense emotional responses, inappropriate emotional responses, rapidly shifting emotions, and difficulty calming down. A subject with emotional dysregulation may experience frequent mood swings, outbursts of anger, or prolonged periods of sadness or anxiety, often reacting disproportionately to events that others would consider minor. A subject with emotional dysregulation may form maladaptive associations between certain stimuli and emotional responses. Emotional dysregulation often exacerbates cognitive distortions,Attorney Docket No. 130948.00011such as catastrophizing or dichotomous thinking, which in turn reinforces maladaptive learning. For example, intense emotions can make it more difficult to challenge irrational thoughts, leading to a cycle in which distorted thinking and emotional dysregulation reinforce each other.

[0076] Excipient: As used herein, the term excipient refers to substances, other than the therapeutic agent, that are used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are well known to those skilled in the art of pharmaceutics; and therefore, have not been listed here. A nonlimiting list of common pharmacally acceptable excipients can be found in the US Food and Drug Administration's Inactive Ingredient Database.

[0077] Extinction learning: As used herein, the term extinction learning refers to the process by which a subject reduces or eliminates a learned response. When the learned response is due to reinforced associations between a stimulus and a response, extinction learning involves the reduction or elimination of the association between the stimulus and the response, thereby leading to the reduction or elimination of the learned response. When the learned response occurs in the absence of the stimulus, extinction learning involves the alteration or disruption of the conscious or unconscious cognitive patterns maintaining the response, thereby leading to the reduction or elimination of the learned response. In a disorder of maladaptive learning, the learned response is maladaptive and may be a counterproductive behavior, thought pattern, or emotional reaction. Treatment of the disorder of maladaptive learning requires extinction of the maladaptive response through the process of extinction learning. Extinction learning may be facilitated by pharmacotherapy, psychotherapy, or a combination of pharmacotherapy and psychotherapy. The present disclosure provides novel pharmacotherapeutic methods to facilitate extinction learning.

[0078] Feature of maladaptive learning: As used herein, the tenn feature of maladaptive learning refers to a clinically assessable characteristic, behavior, or cognitive pattern exhibited by a subject that indicates the presence of maladaptive learning processes. Features of maladaptive learning in the subject may involve maladaptive responses to stimuli, reinforcement of harmful behaviors or thoughts, dysfunctional associations between stimuli and outcomes, or impairments in cognitive or emotional regulation that cause or result from maladaptive coping mechanisms.

[0079] Incentive salience: As used herein, the term incentive salience refers to the desirability that a subject attributes to a stimulus based on its association with a rewarding outcome. The subject experiences incentive salience as craving or wanting the stimulus. Unlike the sensation of liking, which is the immediate pleasure gained from a rewarding stimulus, incentive salience refers to a motivational state in which the sensation of craving or wanting drives the subject to seek out the stimulus. Attribution of unfounded or exaggeratedAttorney Docket No. 130948.00011desirability to the stimulus can adversely affect motivational prioritization and distort cognitive processes, causing the subject to irrationally believe that obtaining the desired stimulus is important for their well-being or survival, thereby overriding logical decision-making. Incentive salience can also reinforce and perpetuate harmful behavior or thought patterns, making them more automatic and difficult to change, leading to compulsions such as addiction or obsessive routines.

[0080] Influenced by maladaptive learning: As used herein, a mental disorder, syndrome, or symptom being ‘‘influenced by maladaptive learning” means that maladaptive learning, including one or more features of maladaptive learning, contributes to the development, maintenance, exacerbation, or recurrence of one or more symptoms, behaviors, or functional impairments in a subject. In some embodiments, such influence may be evidenced by one or more clinically assessable features of maladaptive learning, including, without limitation, negative or positive reinforcement of harmful behaviors or thoughts, incentive salience leading to compulsive actions, maladaptive stimulus-response associations, inhibitory’ control dysfunction, compulsive behaviors, cognitive distortions, avoidance behaviors, emotional dysregulation, learned helplessness, conditioned fear responses, interpersonal dysfunction, response perseveration, maladaptive coping mechanisms, behavioral rigidity, or perceptual rigidity. ‘Influenced by” does not require maladaptive learning to be the sole cause or the primary' cause of the mental disorder, syndrome, or symptom.

[0081] Inhibitory control dysfunction: As used herein, the tenn inhibitory control dysfunction refers to the impaired ability to suppress inappropriate or unwanted behaviors, thoughts, or emotions. A subject with inhibitory control dysfunction struggles to regulate their impulses or refrain from actions that are detrimental to themselves or others. Tire subject may act on harmfill impulses without considering the consequences, such as reacting with aggression during minor conflicts or failing to resist the urge to engage in risky behaviors. The subject may struggle to suppress maladaptive behaviors once they have been learned. For example, the subject might repeatedly engage in substance use or other impulsive actions because they cannot effectively inhibit these behaviors despite experiencing negative outcomes. When faced with stressful situations or triggers, the subject may default to maladaptive behaviors due to a lack of self-regulation needed to implement healthier coping strategies. Inhibitory control dysfunction often leads to a preference for immediate gratification over long-term benefits. This preference reinforces maladaptive learning because the subject is more likely to engage in behaviors that provide short-term relief or pleasure, such as overeating, substance use. or compulsive shopping, rather than behaviors that require delayed gratification.

[0082] Interpersonal dysfunction: As used herein, the tenn interpersonal dysfunction refers to difficulties in forming and maintaining healthy relationships. Interpersonal dysfunction is often rooted in learned negative interaction patterns and reinforced by maladaptive responses to interpersonal conflict. A subject withAttorney Docket No. 130948.00011interpersonal dysfunction may struggle with trust, communication, or empathy, leading to arguments, social isolation, and challenges in building supportive relationships.

[0083] Learned helplessness: As used herein, the term learned helplessness refers to a psychological state in which a subject has learned to believe they are powerless to change their situation due to repeated exposure to uncontrollable events. Learned helplessness affects the subject’s motivation, cognition, and emotional responses, leading the subject to believe they have no control over the outcomes of their actions, even when control is possible. In disorders of maladaptive learning, learned helplessness can become entrenched, leading to passivity and a lack of initiative. The subject with learned helplessness may exhibit signs of resignation and avoidance of challenges because they believe their actions will not make a difference, which can perpetuate a cycle of inactivity and depression. The subject with learned helplessness may express the belief that their actions are futile, complain of low motivation, or exhibit symptoms of depression or anxiety when faced with challenges.

[0084] Maladaptive learning: As used herein, the term maladaptive learning refers to the process by which a subject acquires or reinforces behaviors, thoughts, or emotional responses that are detrimental to their wellbeing or functioning. Maladaptive learning may occur through the reinforcement of harmful behaviors or thoughts, dysfunctional associations between stimuli and outcomes, or impairments in cognitive and emotional regulation that result in maladaptive coping mechanisms. Maladaptive learning leads to patterns that are inflexible or counterproductive, often exacerbating stress, anxiety, and other psychological issues.

[0085] Negative reinforcement: As used herein, the term negative reinforcement refers to tire strengthening of a behavior or thought pattern through the removal of an unpleasant stimulus. Often this type of reinforcement affects behaviors such as engaging in a particular action to avoid or stop an adverse condition. For example, a behavior of self-harm is reinforced in a subject who is engaging in self-harm to relieve emotional pain or taking painkillers to relieve a headache. As used herein, negative reinforcement also encompasses the strengthening of avoidance behaviors through association with unpleasant stimuli. This means that the presence of an unpleasant stimulus can increase the likelihood of certain associated behaviors or situations being avoided in the future to prevent experiencing the unpleasant stimulus again.

[0086] Perceptual rigidity: As used herein, the term perceptual rigidity refers to the inflexible adherence to specific interpretations or thought patterns, despite changing circumstances or the absence of a logical basis for such persistence. A subject exhibiting perceptual rigidity may struggle to alter their interpretations based on new information or feedback and may become distressed when confronted with perspectives or evidence that challenge their fixed viewpoints. In maladaptive learning, perceptual rigidity results in a fixed, oftenAttorney Docket No. 130948.00011negative view of oneself, others, or the world. The subject with perceptual rigidity may persistently view themselves as incapable or unworthy despite evidence to the contrary, or maintain a distorted view of social interactions, leading to persistent interpersonal conflicts and self-esteem issues.

[0087] Pharmaceutically acceptable: As used herein, the term pharmaceutically acceptable refers to substances used in a drug product that are considered generally safe (i.e., non-toxic and otherwise biocompatiblc in the manner and amounts employed, commensurate with a reasonable benefit / risk assessment) for human pharmaceutical use.

[0088] Positive reinforcement: As used herein, the term positive reinforcement refers to the strengthening of a behavior or thought pattern through the presentation of a pleasant or rewarding stimulus. Often this type of reinforcement affects behaviors. Subjects may learn and perpetuate harmful or non-beneficial behaviors when those behaviors are inadvertently reinforced by positive outcomes. In substance use disorder, positive reinforcement occurs when the pleasurable effects of a drug encourage continued use. thereby reinforcing the behavior of drug consumption. Positive reinforcement encompasses the introduction of any desirable outcome that increases the likelihood of a behavior being repeated, whether it be tangible rewards, praise, or any other form of positive feedback that encourages continuation of the behavior.

[0089] Response: As used herein, response refers to any behavioral, emotional, or cognitive reaction elicited by a stimulus, encompassing both conscious and unconscious actions or changes in a subject’s thought patterns that result from exposure to an external or internal event, object, or condition.

[0090] Response perseveration: As used herein, the term response perseveration refers to the repetition of a particular response despite the absence or cessation of a stimulus. A subject exhibiting response perseveration may have difficulty switching thoughts or behaviors in response to changing situations. Tire subject exhibiting response perseveration may ruminate (e.g., continuously dwelling on a specific worry) or continue a specific action long after the relevance of the stimulus has ended (e.g., compulsive actions such as dermatillomania), demonstrating inflexibility in thought or behavior.

[0091] Stimulus: As used herein, stimulus or its plural form, stimuli, refers to any external or internal event, object, or condition that elicits a psychological response (i.e., behavioral, emotional, or cognitive reaction) from a subject. Stimulus is used herein synonymously with trigger and cue. These terms are used interchangeably to describe factors that can elicit or modify the subject's response patterns.

[0092] Stimulus-response associations: As used herein, the term stimulus-response associations refers to learned connections in which specific environmental triggers or cues (stimuli) elicit specific behavioral,Attorney Docket No. 130948.00011emotional, or cognitive reactions (response), often leading to automatic or habitual patterns of action and corresponding reaction. These entrenched patterns are resistant to alteration, even when harmful. Maladaptive stimulus-response associations hinder learning new, healthier responses and interfere with the extinction of dysfunctional responses. For example, overgeneralization of responses to various stimuli can lead to reinforcement of adverse thought patterns that may manifest as or exacerbate mental disorders such as anxiety or depression. Subjects suffering from anxiety may develop associations between certain situations and fear responses, leading to avoidance behaviors that perpetuate the anxiety. Recognition of maladaptive stimulusresponse associations in a subject involves observing repetitive, automatic responses to specific stimuli that do not seem to change despite negative outcomes or attempts at intervention.

[0093] Subject or Subject in need thereof: As used herein, the term subject or subject in need thereof refers to any human. Tire terms subject, patient, individual, and person may be used interchangeably herein. When the subject has taken part in or is taking part in a research study, the term participant may also be used. Tire terms subject, subject in need thereof, patient, individual, person, and participant include those who have symptoms of a mental health disorder, a substance use disorder, or a condition related to the same, whether or not the subject is diagnosed with such a disorder. Moreover, these terms shall likewise refer to subjects who have received treatment or therapy in the past, are currently receiving treatment or therapy, or who may receive treatment or therapy in the future for a mental health disorder or substance use disorder. The disclosed methods of treatment can be modified to treat multiple subjects at once, including couples, families, or groups. Hence, these terms will be understood to also mean two or more subjects.

[0094] Symptom: As used herein, the term symptom refers to any physical or mental abnormality experienced or exhibited by a subject. Symptoms can vary in origin, intensity, duration, and impact on the subject's daily functioning. The tenn symptom encompasses clinical manifestations that indicate the presence of a disease, disorder, or syndrome. The term symptom also encompasses clinical manifestations that indicate a disease, disorder, or syndrome may develop.

[0095] Syndrome: As used herein, the term syndrome refers to a set of symptoms (i.e., a consistent and recognizable pattern of clinical manifestations) experienced or exhibited by a subject that characterize a certain abnormal state of physical or mental health, such as a disease or disorder. The term syndrome encompasses symptomology that indicates the subject may have an increased chance of developing a disease or disorder. The syndrome may be associated with a specific underlying cause or may represent a group of related causes without a single identifiable origin.Attorney Docket No. 130948.00011

[0096] Test Article: As used herein, the term Test Article is a moniker for the active agent being tested and is used to enable blinding.

[0097] Therapeutically effective amount: As used herein, the term therapeutically effective amount refers to an amount of an active ingredient sufficient to elicit a desired prophylactic, therapeutic, or pharmacological effect in a subject. Such effects include, but are not limited to, alleviation of symptoms, modulation of a pathological process, facilitation of extinction learning, attenuation of maladaptive stimulus -response associations, stabilization of neurophysiological function, or enhancement of treatment outcomes. Tire therapeutically effective amount may vary based on factors such as the subject’s medical condition, severity of symptoms, dosage regimen, route of administration, and individual pharmacokinetic or pharmacodynamic response.Pharmacal Preparations

[0098] The present disclosure relates to pharmaceutical preparations comprising bromantane or an analogue of bromantane, and methods of using said preparations for pharmacotherapy in the treatment of StUD or other disorders of maladaptive learning.

[0099] In one aspect of the disclosure, a subject who presents with symptoms of a mental disorder or syndrome is identified as having one or more features of maladaptive learning that cause, arise from, or exacerbate the subject’s symptoms.

[0100] Nonlimiting examples of features of maladaptive learning include negative or positive reinforcement of harmful behaviors or thoughts, incentive salience leading to compulsive actions, maladaptive stimulusresponse associations, inhibitory control dysfunction, compulsive behaviors, cognitive distortions, avoidance behaviors, emotional dysregulation, learned helplessness, conditioned fear responses, interpersonal dysfunction, response perseveration, maladaptive coping mechanisms, behavioral rigidity, or perceptual rigidity.

[0101] Maladaptive learning occurs when a subject acquires and reinforces harmful behaviors or thought patterns rather than beneficial ones, due to various biological, psychological, or environmental factors.Maladaptive learning may cause the subject to experience persistent difficulties in functioning and hinder the subject’s ability to cope with life's challenges effectively. Maladaptive learning can manifest as a canonical mental disorder that is diagnosable according to established clinical criteria (e.g.. Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD)) or as a syndrome thatAttorney Docket No. 130948.00011does not meet the specific diagnostic criteria for a disorder but still involves a consistent set of maladaptive behaviors or thought patterns.

[0102] In embodiments, a disorder of maladaptive learning as described herein does not necessarily correspond to, and is not limited by, the diagnostic categories used to define canonical mental disorders. A disorder of maladaptive learning may be present as an etiological component, contributing factor, or maintaining mechanism within one or more canonical mental disorders, and in such embodiments the disorder of maladaptive learning may be treated by facilitating extinction learning even if the subject also meets criteria for a canonical mental disorder. In other embodiments, a disorder of maladaptive learning may be identified and treated as a distinct condition that does not fit neatly within, or is not fully captured by, canonical diagnostic classifications, including where the maladaptive learning phenotype is subclinical, transdiagnostic, behaviorally defined, or otherwise not codified as a standalone DSM or ICD diagnosis. Accordingly, references herein to disorders of maladaptive learning encompass (i) maladaptive learning phenotypes occurring within subjects diagnosed with a canonical mental disorder, maladaptive learning phenotypes occurring within subjects considered to be suffering from a syndrome and (iii) maladaptive learning phenotypes occurring in subjects who are neither considered to be suffering from a syndrome nor meet diagnostic criteria for a canonical mental disorder. This is illustrated in [FIG. 28] .

[0103] Nonlimiting examples of mental disorders in which maladaptive learning may contribute to the development, maintenance, or exacerbation of symptoms include: substance-related and addictive disorders (e.g., substance use disorders, gambling disorders, cyber / technology addiction), conduct and impulse control disorders (e.g., oppositional defiant disorder, intermittent explosive disorder, kleptomania, pyromania), trauma- and stressor-related disorders (e.g., post-traumatic stress disorder, acute stress disorder, complex post-traumatic stress disorder, adjustment disorders), anxiety disorders (generalized anxiety disorder, panic disorder, social anxiety disorder, specific phobias, obsessive-compulsive disorder), mood disorders (e.g., major depressive disorder, persistent depressive disorder, bipolar disorder), neurodevelopmental disorders (e.g., attention-deficit / hyperactivity disorder), eating disorders (e.g., anorexia nervosa, bulimia nervosa, binge-eating disorder, orthorexia nervosa), personality disorders (e.g., borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder), somatic symptom and related disorders (e.g., somatic symptom disorder, illness anxiety disorder, conversion disorder), or dissociative disorders (e.g.. depersonalization-derealization disorder, dissociative identity disorder).

[0104] Nonlimiting examples of syndromes in which maladaptive learning may contribute to the development, maintenance, or exacerbation of symptoms include: drug or substance withdrawal syndromesAttorney Docket No. 130948.00011(e.g., reward deficiency syndrome, serotonin syndrome, alcohol hangover, stimulant-induced anxiety, drug-induced psychosis, opioid withdrawal syndrome, rebound anxiety from withdrawal of anti-anxiety medications, post-intoxication regret, impulsive decision-making regret), stress-related syndromes (e.g., burnout, chronic fatigue), trauma-related syndromes (e.g., trauma bonding), anxiety-related syndromes (e.g., guilt complex, toxic shame, hypervigilance, hypochondriasis, separation anxiety, social anxiety, performance anxiety, fear of failure, fear of change, fear of public speaking, writers block), circadian rhythm -related syndromes (e.g., premenstrual syndrome, menopause), mood-related syndromes (e.g., affective dysregulation, dysthymia), somatization syndromes (e.g., psychogenic pain, stress -induced skin reactions), impulse control syndromes (e.g., compulsive shopping, trichotillomania, dermatillomania).

[0105] A disorder of maladaptive learning is characterized by specific deficits in learning processes, such as difficulties in extinction learning and persistent maladaptive responses to cues or triggers. Canonical mental disorders or syndromes stereotypically associated with maladaptive behaviors or thought patterns do not necessarily constitute a disorder of maladaptive learning. For example, a subject meeting diagnostic criteria for depression may exhibit symptoms due to maladaptive learning processes, such as the inability to extinguish negative thought patterns in response to certain stimuli, making their depression a disorder of maladaptive learning. However, depression can also result from other factors which do not involve maladaptive learning, such as neurobiological imbalances, genetic predispositions, or environmental stressors. Tire distinction between mental disorders or syndromes influenced by maladaptive learning and those same disorders or syndromes caused by other factors is important because identifying the underlying mechanisms that contribute to the development, maintenance, or exacerbation of symptoms enables the selection of correctly targeted therapeutic interventions, thereby ensuring effective treatment. The therapeutic intervention disclosed herein entails pharmacotherapy to address deficits in extinction learning that contribute to a mental disorder or syndrome, as opposed to alleviating symptomatic manifestations by other means.

[0106] In an embodiment, a subject who presents with symptoms of a mental disorder or syndrome is identified as having one or more features of maladaptive learning based on clinical assessment. Clinical assessment may involve the use of scales, inventories, questionnaires, or interviews to determine the extent to which said features are responsible for the subject’s symptoms, benchmark levels of distress or functional impairment, and elucidate contributing or confounding factors. Nonlimiting examples of clinical assessment tools that may be used for this purpose include Maladaptive Behavior Index (MB I), Addiction Severity Index (AS1), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Cognitive Emotion Regulation Questionnaire (CERQ), Functional Analysis Screening Tool (FAST), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Minnesota Multiphasic Personality Inventory (MMPI), Behavior Assessment System forAttorney Docket No. 130948.00011Children (BASC), Connor-Davidson Resilience Scale (CD-RISC), Structured Clinical Interview for DSM-5 (SCID-5), Obsessive-Compulsive Inventor -Revised (OCI-R), or Child Behavior Checklist (CBCL). To achieve a differential diagnosis for a disorder of maladaptive learning, criteria may be applied that distinguish a subject whose mental disorder or syndrome is materially influenced by maladaptive learning from a subject whose mental disorder or syndrome is materially influenced by other factors (c.g.. genetic predispositions, neurobiological abnormalities, acute environmental stressors), thereby guiding targeted treatment strategies, including the use of pharmacotherapy to facilitate extinction learning.

[0107] In some embodiments, a subject who presents with symptoms of a mental disorder or syndrome is identified as having one or more features of maladaptive learning based on the application of diagnostic criteria for StUD. StUD is diagnosed by clinical assessment. Nonlimiting examples of clinical assessment tools that may be used for this purpose include Structured Clinical Interview for DSM-5 (SCID-5), Addiction Severity Index (ASI), Drug Abuse Screening Test (DAST), Timeline Followback (TLFB), Substance Use Disorder Diagnostic Schedule (SUDDS), Mini International Neuropsychiatric Interview (MINI), Clinical Institute Withdrawal Assessment for Stimulants (CIWA-Stimulant). CAGE-AID Questionnaire (Adapted to Include Drugs), Composite International Diagnostic Interview (CIDI), Brief Substance Craving Scale (BSCS). A diagnosis of StUD constitutes diagnosis of a disorder of maladaptive learning. During clinical assessment, the subject’s patterns of stimulant use, severity of dependence to stimulants, withdrawal symptoms, and exposure to potential relapse triggers are evaluated. Information from the evaluation is used to develop a treatment strategy involving pharmacotherapy that facilitates extinction learning to alleviate withdrawal syndrome and prevent relapse.

[0108] In some embodiments, a subject who intends to discontinue or has recently discontinued one or more medications that may have dependence liabilities is identified as having one or more features of maladaptive learning based on a risk assessment. In the case of planned discontinuation, the risk assessment considers anticipated psychological and physiological impacts of discontinuation to determine the likelihood that the subject will experience withdrawal syndrome. In the case of recent discontinuation, the risk assessment considers the severity and trajectory' of acute withdrawal symptoms the subject is experiencing to determine the likelihood that the subject will develop protracted withdrawal syndrome. If the risk of the subject developing withdrawal syndrome is high, pharmacotherapy that facilitates extinction learning is administered during the transition period to mitigate withdrawal symptoms and dependence.

[0109] Prescription medications that may have dependence liabilities or are known to cause withdrawal symptoms when discontinued span a variety of drug classes, including but not limited to, antidepressants (c.g, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclicAttorney Docket No. 130948.00011antidepressants), anxiolytics (e.g., benzodiazepines, non-benzodiazepine hypnotics, beta blockers), sedatives, anesthetics (e.g., ketamine, phencyclidine, eticyclidine), antipsychotics, stimulants (e.g., amphetamine, methylphenidate), and pain medications (e.g. opioids, gabapentinoids).

[0110] In some embodiments, stimulants that may be associated with misuse, addiction, dependence, compulsive use, withdrawal, craving, relapse, or other maladaptive reinforcement phenotypes include, by way of nonlimiting example, amphetamine type stimulants and related phcncthylamincs, such as amphetamine, dextroamphetamine, methamphetamine, lisdexamfetamine, fenethylline, 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA); phenidate stimulants, such as methylphenidate and dexmethylphenidate; tropane stimulants, such as cocaine and cocaine analogues; synthetic cathinones and related pyrrolidinophenones, such as cathinone, methcathinone, mephedrone, methylone, 3,4-methylcnedioxypyrovalcrone (MDPV), alpha pyrrolidinopentiophenone (alpha PVP), and related analogues; piperazine stimulants, such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP); oxazoline and aminorex type stimulants, such as aminorex, methylaminorex, and related analogues; nootropics and racetams such as piracetam, aniracetam, oxiracetam. phenylpiracetam: other stimulant agents that increase wakefulness or psychomotor activation, such as ephedrine, pseudoephedrine, cathine, and other sympathomimetic amines; xanthines, such as caffeine, theophylline, and theobromine; and wakefulness promoting agents, such as modafinil, annodafmil, and adrafmil. In some embodiments, the foregoing includes pharmaceutically acceptable salts, solvates, stereoisomers, metabolites, prodrugs, and structural analogues of any of the foregoing stimulants.

[0111] In some embodiments, a subject who presents with symptoms of a mental disorder or syndrome is identified as having one or more features of maladaptive learning based on an empirical treatment approach. Nonlimiting examples of circumstances that may prompt this approach include those in which there is symptom alignment with a disorder of maladaptive learning, a lack of alternative treatment options, treatment resistance is observed or other treatment options have failed, greater health risk associated with other treatment options, potential benefit for adjunct therapy, or potential benefit in the treatment of one or more comorbidities. In the empirical treatment approach, pharmacotherapy that facilitates extinction learning is administered without knowing the underlying cause of the symptoms. During the first week of treatment, the subject’s initial response is monitored through regular assessments of symptom changes and side effects to determine the effectiveness and safety of the pharmacotherapy. If the treatment is effective, at least some involvement of maladaptive learning processes may be inferred, and continuation of the pharmacotherapy may be indicated.Attorney Docket No. 130948.00011

[0112] A pharmacotherapy that facilitates extinction learning enhances a subject’s ability to unlearn maladaptive behaviors or thought patterns by weakening previously reinforced associations between stimuli and responses. By making it easier for the subject to disassociate learned cues from their maladaptive responses, said phannacotherapy helps reduce the emotional and behavioral impact of triggers. This process is particularly beneficial in treating conditions in which maladaptive learning plays a role in symptom maintenance and relapse, such as substance use disorders, specific subsets of anxiety disorders, and specific subsets of stress-related disorders. Said pharmacotherapy comprises three key components: a pharmaceutical preparation of a therapeutic agent, a route of administration, and a dosing regimen.

[0113] In another aspect of the disclosure, a phannacotherapy that facilitates extinction learning comprises a pharmaceutical preparation of a therapeutic agent, wherein the therapeutic agent is bromantane or an analogue of bromantane.

[0114] In some embodiments, the therapeutic agent is bromantane [FIG. 1] .

[0115] Bromantane may be synthesized using various established methods known in the art.

[0116] By way of example, one method used to synthesize bromantane is described as follows. Parabromoformanilide (20 g, 100 mmol) was combined with bromoadamantane (10 g, 46 mmol) and stirred at 190 °C for 3 hours. The mixture was cooled to room temperature and stirring was continued as 150 mL of 13 % HClaq was added. Tire mixture was heated again to reflux for 1 hour. Upon cooling to room temperature, 5 M NaOH was added to neutralize. Then the mixture was extracted with several portions of DCM. The extracts were pooled, washed twice with water, and dried over anhydrous Na2SC>4. Stripping the solvent with a rotovap gave the crude product as a solid, which was then purified by recrystallization in acetonitrile. Yield of bromantane free base as a white solid was 55% (7.9 g, 26 mmol) with purity >99% by High Performance Liquid Chromatography (HPLC). Nuclear magnetic resonance (NMR): 'HNMR(700 MHz, DMSO-d6) 8 7.15 (d, 2H), 6.58 (d, 2H), 5.73 (d, 1H), 3.41 (m, 1H), 2.02 (d, 2H), 1.89 (s, 2H), 1.81 (m, 6H), 1.70 (s, 2H), 1.48 (d, 2H), [FIG. 3], The polymorphic fonn obtained was found to be thennodynamically stable and was named Form I. This form appeared as birefringent plates by polarized light microscopy (PLM) [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothermic event occurring at 110 °C [FIG. 5], and produced a unique powder X-ray diffraction (PXRD) pattern as shown in [FIG.6],

[0117] In some embodiments, the therapeutic agent is an analogue of bromantane. Nonlimiting examples of analogues include constitutional isomers (tautomers, regioisomers, skeletal isomers, functional group isomers, metamers, or ring-chain isomers), stereoisomers (geometric isomers, enantiomers, diastereomers, or conformational isomers), isotopes, prodrugs, metabolites, precursors, or derivatives of bromantane.Attorney Docket No. 130948.00011

[0118] In some embodiments, bromantane, or an analogue of bromantane is a compound of the general structure Formula I shown in [FIG. 7] and shown below.

[0119] The molecular scaffold includes an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L). Ri, R2, and R3 are substituents on A that are independently selected from hydrogen, halogen (X = F, Cl, Br, or I), hydroxide, methoxide, methyl, or ethyl. R4, Rs, and Rs are substituents on B that are independently selected from hydrogen, halogen (X = F, Cl, Br, or I), hydroxide, methoxide, methyl, ethyl, or fused 5-member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane). L is independently selected from amine, amide, or imine.

[0120] In some embodiments, an analogue of bromantane is a constitutional isomer (tautomer, regioisomer, skeletal isomer, functional group isomer, metamer, or ring -chain isomer), stereoisomer (geometric isomer, enantiomer, diastereomer, or confonnational isomer), isotope, prodrug, metabolite, or precursor of a structure described by Formula I.

[0121] Tire therapeutic agent is responsible for the pharmacodynamic effect, whereas a drug substance is the physical form of the therapeutic agent used in the pharmacal preparation and has distinct physicochemical properties (e.g., solubility, stability) that affect pharmacokinetics (e.g.. absorption rate, variability in absorption, bioavailability). The drug substance comprises the therapeutic agent and may include one or more co-formers. The distinct physicochemical properties of the drug substance arise from its morphology and the nature of the co-former. The morphology of the drug substance may be either amorphous (non-cr stallinc), polymorphic (thermodynamically stable or mctastablc crystal fomis), or mesomorphic (liquid crystals).

[0122] In another aspect of the disclosure, the therapeutic agent is in the form of a drag substance, wherein the morphology of the drag substance is controlled and defined.Attorney Docket No. 130948.00011

[0123] In some embodiments, the therapeutic agent is bromantane, and the form of the drug substance is a free base with Form I morphology, wherein Form I is the thermodynamically stable polymorphic crystal form.

[0124] In some embodiments, the drug substance is a salt, ionic liquid, co-crystal, hydrate, solvate, complex, conjugate, or prodrug of the therapeutic agent. In some embodiments, the drug substance is a salt, ionic liquid, hydrate, solvate, complex, conjugate, or prodrug of the therapeutic agent.

[0125] In some embodiments, the drug substance is a pharmaceutically acceptable salt or mixture of salts of bromantane. Nonlimiting examples include those wherein the pharmaceutically acceptable salt is selected from acetate, aspartate, benzene sulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate. malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, tosylate, or a mixture thereof.

[0126] The formation of a salt and its physicochemical properties cannot be easily predicted because each potential counterion interacts uniquely with the therapeutic agent. Empirical should be used. A salt screen was performed with bromantane that explored 18 counterions in 6 different solvent systems and employed a variety of crystallization methods. Results from the salt screen are shown in [FIG. 8], Bromantane was found to fonn crystalline salts with the following counterions: chloride, maleate, oxalate, sulfate, methanesulfonate, phosphate, tosylate, and ethanedisulfonate.

[0127] By way of example, one method used to form a hydrochloride salt of bromantane is described as follows. The free base (1.0 g) was dissolved in ether. Dry hydrogen chloride gas was then bubbled through the solution until the precipitation of solids ceased. The solids were collected by fdtration and recrystallized in ethanol. Final yield was 1.1 g of bromantane hydrochloride as a white solid, crystal Form I.

[0128] By way of example, another method used to form a hydrochloride salt of bromantane is described as follows. Ethanol (20 rnL) was acidified with 150 pL of 37% HClaq. Then 0.50 g of the free base was added. Tire mixture was stirred until the solids were dissolved. Tire solution was transferred to a rotovap to strip the solvents, leaving white crystalline solids. The solids were collected, rinsed once with cold ethanol, and dried. Final yield was 0.54 g of bromantane hydrochloride, crystal Form I.Attorney Docket No. 130948.00011

[0129] Bromantane hydrochloride had a characteristic IRband for NIL at 3500-3400 cm1. The ionization state of the amine was also evident by NMR.]H NMR (400 MHz, DMSO-d6) 57.19 (d, 2H), 6.67 (d, 2H), 3.43 (s, 1H), 2.02 (d, 2H), 1.91 (s, 2H), 1.81 (m, 6H), 1.70 (s, 2H), 1.50 (d, 2H), [FIG. 9], ’H NMR (700 MHz, CDCh) 3 11.18 (broad s, 2H). 7.45 (d, 2H), 7.42 (d. 2H), 3.37 (s, 1H), 2.45 (d, 2H). 2.19 (s. 2H), 1.97 (s, 1H), 1.83 (m. 3H), 1.70 (s. 2H), 1.62 (d, 2H). 1.54 (d, 2H). [FIG. 10J.13C NMR (176 MHz, CDCL) 8 143.38, 133.25, 132.63, 126.49, 123.29, 70.08, 37.22, 37.08, 30.33, 28.89, 26.97, 26.69, 18.41, [FIG. 11], The polymorphic crystal form obtained (Form I) appeared as birefringent prisms by PLM [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothermic event occurring at 233 °C [FIG. 12], and produced a unique PXRD pattern as shown in [FIG. 6],

[0130] By way of example, one method used to form a maleate salt of bromantane is described as follows. The free base (1.0 g) was dissolved in 5.0 mL of acetone at 50 °C. Separately, 0.41 g (1.1 eq.) of maleic acid was dissolved in 5.0 mL of acetone. The acid solution was added dropwise to the solution of freebase while stirring at 250 rpm. Stirring continued while the temperature was held at 50 °C for 2 hr, during cooling to 20 °C, and while the temperature was held again for 10 hr at 20 °C. The resultant suspension was filtered, and the cake was dried to give bromantane maleate as a white solid, crystal Form I.

[0131] Bromantane maleate formed in a 1 : 1 stoichiometric ratio, as was evident by integration of the olefin peak of the counterion at 86.26 in the 'H NMR spectrum. ’H NMR (400 MHz, DMSO-d6) 87.16 (d, 2H), 6.58 (d, 2H), 6.26 (s, 2H). 3.41 (s. 1H), 2.03 (s, 2H), 1.89 (s, 2H), 1.81 (m, 6H). 1.70 (s. 2H), 1.49 (d, 2H), [FIG. 13], The polymorphic crystal form obtained (Form I) appeared as birefringent needles by PLM [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothermic event occurring at 152 °C [FIG. 14], and produced a unique PXRD pattern as shown in [FIG. 6],

[0132] Bromantane oxalate 'H NMR (400 MHz, DMSO-d6) shifts were 87.15 (d, 2H), 6.58 (d, 2H). 3.41 (s.1H), 2.03 (d, 2H), 1.89 (s, 2H), 1.81 (m, 6H), 1.70 (s, 2H), 1.49 (d, 2H), [FIG. 15], The polymorphic crystal form obtained (Form I) appeared as birefringent granules by PLM [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothermic event occurring at 180 °C [FIG. 16], and produced a unique PXRD pattern as shown in [FIG. 6] .

[0133] Bromantane sulfate 'H NMR (400 MHz, DMSO-d6) shifts were 87.19 (d, 2H), 6.65 (d, 2H), 3.43 (s, 1H), 2.01 (d, 2H), 1.90 (s, 2H), 1.81 (m, 6H), 1.70 (s, 2H), 1.50 (d, 2H), [FIG. 17], Tire polymorphic crystal fomi obtained (Fomr I) appeared as birefringent granules by PLM [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothennic event occurring at 214 °C [FIG. 18], and produced a unique PXRD pattern as shown in [FIG. 6] .Attorney Docket No. 130948.00011

[0134] Bromantane methane sulfonate formed in a 1: 1 stoichiometric ratio, as was evident by integration of the peak from the methyl protons of the counterion at 82.34 in the 'HNMR spectrum.1H NMR (400 MHz, DMSO-d6) 87.21 (d, 2H), 6.66 (d, 2H), 3.44 (s, 1H), 2.34 (s, 3H), 2.03 (d, 2H), 1.91 (s, 2H), 1.85 (m, 6H), 1.71 (s, 2H). 1.49 (d, 2H). The polymorphic crystal form obtained (Form I) appeared as birefringent granules by PLM [FIG. 4], underwent melt in a hermetically sealed pan with the peak of the endothermic event occurring at 214 °C [FIG. 19], and produced a unique PXRD pattern as shown in [FIG. 6],

[0135] Four polymorphic crystal forms were found for bromantane phosphate. The PXRD patterns for each form are shown in [FIG. 20], Each form can be accessed by precipitating the salt from tire appropriate solvent. Tire form associated with diffraction Pattern A can be obtained by precipitation from ethyl acetate. The form associated with diffraction Pattern B can be obtained by precipitation from acetone. The form associated with diffraction Pattern C can be obtained by precipitation from tetrahydrofuran. The form associated with diffraction Pattern D can be obtained by precipitation from acetonitrile.

[0136] Two polymorphic crystal forms were found for bromantane tosylate. The PXRD patterns for each are shown in [FIG. 21], Each form can be accessed by precipitating the salt from the appropriate solvent. The form associated with diffraction Pattern A can be obtained by precipitation from either ethanol, acetone, tetrahydrofuran, or acetonitrile. Tire form associated with diffraction Pattern B can be obtained by precipitation from ethyl acetate.

[0137] Two polymorphic crystal forms were found for bromantane ethanedisulfonate. The PXRD patterns for each are shown in [FIG. 21], Each form can be accessed by precipitating the salt from the appropriate solvent. Tire form associated with diffraction Pattern A can be obtained by precipitation from either ethanol, acetonitrile, or ethanol / water (95 / 5 %w / w). The form associated with diffraction Pattern B can be obtained by precipitation from ethyl acetate.

[0138] Tire solubility advantage imparted by a specific salt form of bromantane compared to the free base form cannot be predicted with certainty because the interactions of the counterion with the therapeutic agent and dissolution medium are unique and complex. Empirical testing is necessary. Dynamic Vapor Sorption (DVS) testing was performed to compare the isothermal water sorption and desorption behaviors of bromantane free base Form I [FIG. 22] with that of bromantane hydrochloride Form I [FIG. 23], Tire free base was found to be non-hygroscopic (x < 0.2 %w / w gain at 25 °C and 80 %RH), whereas the hydrochloride salt was found to be moderately hygroscopic (2 < x < 15 %w / w gain at 25 °C and 80 %RH). To compare aqueous solubilities, slurries of each drug substance were prepared in water, and HPLC was used to measure the solution state concentrations of bromantane that resulted in the supernatants after 24 hours of equilibrationAttorney Docket No. 130948.00011at room temperature. The equilibrium solubility of the free base in water was below the detection limit, whereas 0.2 pg / mL of solution state bromantane was measured from equilibration of the hydrochloride salt in water [FIG. 24] Furthennore, the solution state concentration of bromantane resulting from equilibration of bromantane sulfate Form I in water was found to be 0.8 pg / m L. which is four times higher than the solubility advantage conferred by the hydrochloride salt.

[0139] In some embodiments, the therapeutic agent is bromantane, and the fonn of tire drug substance is an amorphous free base.

[0140] In some embodiments, the morphology of the drug substance is controlled by combining the drug substance with one or more pharmaceutically acceptable excipient that functions to inhibit crystallization of the drug substance (i.e., disrupt the crystalline lattice of the drug substance and stabilize the amorphous state). Nonlimiting examples of a composition comprising the drug substance and at least one excipient that functions to inhibit crystallization of the drug substance include Amorphous Solid Dispersions (ASD: e.g., spray dried dispersion, hot melt extrudates, lyophilizates, co-precipitates, amorphous granules, amorphous films, solid inclusion complexes), semi-solid or liquid solutions (e.g., gels, process feed solutions, solutions with organic vehicle components, solutions w ith complexing agents, lipid solutions, polymer solutions, supercritical fluids), or colloidal drug carriers (e.g. nano or micro drug suspensions, nano or micro drug carriers, micelles, liposomes, niosomes, lipid particles, emulsions, self-emulsifying drug delivery systems). Applicable excipients are selected based on their ability to inhibit crystallization of the drug substance, facilitate the drag product manufacturing process, and influence the in vivo drug release profile.

[0141] In some embodiments, the therapeutic agent is bromantane, the form of the drug substance is an amorphous free base, and crystallization of the drug substance is inhibited by preparing an ASD. The ASD is prepared by mixing the drug substance with one or more pharmaceutically acceptable excipients using a suitable technique such that the drug substance is dispersed uniformly at a molecular level within the excipient matrix. Nonlimiting examples of suitable techniques to uniformly disperse the drug substance at a molecular level within the excipient matrix include solvent evaporation (e.g., spray drying, lyophilization), melt mixing (e.g., hot melt extrusion), or high shear mixing / milling / grinding. Nonlimiting examples of the ASD include those wherein the crystallization inhibiting excipient is independently selected from one or more of the following: pharmaceutically acceptable polymers (e.g., polyvinylpyrrolidone, polyvinylpyrrolidone -vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, dextrins, cyclodextrins, methacrylate copolymers, polyethylene glycol, poly(lactic-co-glycolic acid), polyvinyl alcohol, polyvinyl caprolactam -polyvinyl acetate -polyethylene glycol graft copolymer), pharmaceutically acceptable surfactants (e.g.. poloxamer. polysorbate, sorbitan ester, polyoxylAttorney Docket No. 130948.00011castor oil, lecithin, sodium lauryl sulfate, docusate sodium, cetyltrimethylammonium bromide, benzalkonium chloride), pharmaceutically acceptable plasticizers (e.g., triethyl citrate, glycerin, propylene glycol), pharmacally acceptable sugars (e.g., sucrose, glucose, lactose, sorbitol, mannitol, xylitol, trehalose), pharmacally acceptable thermoplastics (e.g., ethylcellulose, polycaprolactone, polymethacrylate, polylactide, poly(ethylene-co-vinyl acetate)). The ratio of drug substance mass to total excipient mass is between 0.1 and 10. Selection of suitable excipients and optimization of ratios involves complementary rational design and empirical screening approaches, wherein permutations are systematically narrowed based on known physicochemical properties and theoretical interactions to reduce the number of permutations subjected to practical experimentation.

[0142] To prepare an ASD of bromantane by solvent evaporation, the drug substance and one or more crystallization inhibiting excipient are intimately mixed by dissolving both the drug substance and excipients in a volatile solvent or solvent system. Then the solvent is evaporated to recover the uniformly dispersed drug substance and excipient(s) as the ASD. Nonlimiting examples include those wherein the solvent is selected from one or more of the following: ethanol, methanol, isopropanol, acetone, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, methylethylketone, water, or a mixture thereof. The equilibrium solubility of bromantane free base Form I in various organic solvents is shown in [FIG. 25],

[0143] By way of example, an ASD of bromantane was prepared by solvent evaporation through spray drying as follows. A feed solution containing bromantane and copovidone at a ratio of 50 / 50 %w / w was prepared by dissolving 6 g of copovidone and 6 g of bromantane free base Form I in 100 mb of acetone. The feed solution was aerosolized in a lab scale spray drier at a rate of 5 mL / min through a 0.5 mm atomizer at a pressure of 2 bar, with the chamber air inlet temperature set to 70 °C. The ASD, recovered as white pow der from the cyclone collector, was confirmed to be amorphous by PXRD [FIG. 26] and PTM.

[0144] To prepare an ASD of bromantane by melt mixing, the drug substance and one or more crystallization inhibiting excipient are mechanically mixed in a sealed vessel while heating to a temperature 2-10 °C above the transition temperature which results in a molten state. Mixing of the components in the molten state continues until a homogenous solution is observed. The homogeneous solution is then cooled to room temperature to solidify the uniformly dispersed drug substance and excipient as the ASD.

[0145] In another aspect of the disclosure, a pharmaceutical preparation of the therapeutic agent is a dosage fomi comprising a therapeutically effective amount of the drug substance and may include one or more pharmacally acceptable excipients. Nonlimiting examples of the dosage fonn include tablets, capsules, softgels, gums, pastilles, chewables. lozenges, solutions, syrups, suspensions, emulsions, ampules, granules,Attorney Docket No. 130948.00011powders, cachets, sprays, aerosols, foams, gels, pastes, creams, suppositories, films, and patches. The excipients may include, but are not limited to, binders, fillers, diluents, disintegrants, lubricants, glidants, preservatives, stabilizers, solubilizing agents, wetting agents, emulsifiers, buffering agents, coloring agents, flavoring agents, or coating materials. Specific excipients that are suitable for each type of dosage form and route of administration would be known to a person skilled in the art of pharmaceutics.

[0146] In another aspect of the disclosure, a pharmaceutical preparation of the therapeutic agent is administered by one or more enteral or parenteral delivery route. The enteral delivery route involves absorption of the therapeutic agent in the gastrointestinal tract (oral - through the mouth or rectal - into the rectum). Nonlimiting examples of parenteral delivery routes include oral mucosal (e.g., sublingual, sublabial, and buccal), intranasal, inhalation (e.g., intratracheal, pulmonary), transdermal, intradermal, subcutaneous, intramuscular, intravenous, intrathecal, intraperitoneal, epidural, intravaginal, intracavemous, and intravitreal.

[0147] In some embodiments, the route of administration for bromantane is oral mucosal, wherein the pharmaceutical preparation releases the therapeutic agent in the oral cavity to enable transmucosal absorption, thereby bypassing first-pass extraction and shortening the onset of therapeutic effect.

[0148] By way of example, a tablet dosage form containing 20 mg of stabilized amorphous bromantane free base was prepared. First, a 50 / 50 %w / w ASD of bromantane in copovidone was prepared from crystalline bromantane free base Form I by spray drying as described above. The ASD was then blended at 40 %w / w with 39 / 20 / 1 %w / w starch, microcrystalline cellulose, and magnesium stearate. Tablets with core weights of 100 mg were formed from the blend by direct compression at 15 kN. An image of the tablet dosage form labeled as TA2 is shown in [FIG. 27] .

[0149] By way of example, a tablet dosage form containing 22.4 mg of crystalline bromantane hydrochloride salt was prepared. First, the drug substance (bromantane hydrochloride salt Form I) was prepared from bromantane free base using acidified ethanol as described above. Tire drug substance was blended at 22.4 %w / w with 39 / 37.6 / 1 %w / w starch, microcrystalline cellulose, and magnesium stearate. Tablets with core weights of 100 mg were formed from the blend by direct compression at 15 kN. An image of the tablet dosage form labeled TA3 is shown in [FIG. 27] .

[0150] By way of example, an oral thin film (OTF) dosage form containing 20 mg of amorphous bromantane free base was prepared. A mixture of 20 / 62 / 16 / 2 %w / w crystalline bromantane free base Form I, pullulan. glycerin, and polysorbate was stirred in a sealed vessel while heating until a homogenous melt was observed. The warm melt was spin coated to a uniform thickness of 0.2 mm and trimmed to obtain a film with a mass of 100 mg. The film was confirmed to be amorphous, appeared isotropic (nonbirefringent) by PLM andAttorney Docket No. 130948.00011exhibited a characteristic amorphous halo by PXRD [FIG. 26] . An image of the OTF dosage form labeled TAI is shown in [FIG. 27],

[0151] A dissolution experiment was conducted to measure the in vitro kinetic solubility profiles of the OTF dosage form containing amorphous bromantane free base (TAI), the tablet dosage form containing an ASD of bromantane free base (TA2), and the tablet dosage form containing bromantane hydrochloride salt (TA3) that were prepared as described above. Solubilized bromantane was measured over time by monitoring UV absorbance of the dissolution medium at Z - 265 nm. The kinetic solubility profiles were compared against that of a standard tablet dosage from containing 20 mg of crystalline bromantane free base (TA4). The standard tablet was prepared by direct compression of a 20 / 39 / 40 / 1 %w / w blend of bromantane free base Form I, starch, microcrystal I inc cellulose, and magnesium stearate at 15 kN. The dissolution medium was simulated saliva, pH 6.8 and 37 °C. The order of performance for the pharmaceutical preparations tested was TAI > TA2 > TA3 > TA4, indicating that the standard tablet (TA4) would produce the slowest onset of therapeutic effect and lowest bioavailability in vivo. Results from the dissolution experiment are shown in [FIG. 27],

[0152] In some embodiments, a method for treating a subject suffering from StUD is provided, wherein a pharmaceutical preparation of bromantane is administered as interventional pharmacotherapy to alleviate cravings and facilitate extinction learning. Tire method comprises instructing the subject to refrain from using the stimulant(s) of concern and administering bromantane to the subject at a dose ranging from 25 mg to 100 mg per day. The initial daily dose amount may be determined, for example, based on the administration route, time interval between doses, body weight of the subject, and sex of the subject. Administration of bromantane is carried out over a treatment period of 1 to 6 weeks, depending on the severity of the disorder, the subject's response to the treatment, and the clinical judgment of the healthcare provider. During the course of treatment, the subject's progress is monitored regularly to assess the effectiveness of the intervention and to make any necessary adjustments to the dosage or duration of therapy.

[0153] A therapeutically effective amount of bromantane administered by oral mucosal, gastrointestinal, or a combination of oral mucosal and gastrointestinal routes may range from 10 mg to 200 mg per day. The effects from once-daily oral administration of a tablet dosage form containing 50 mg of bromantane free base Form I gradually increase from the first day of dosing, reaching a maximum after approximately 3 to 14 continuous days of dosing. Thereafter, the therapeutic effect may become durable, allowing for a reduction in the maintenance dose or an increase in the time between maintenance doses. Given this treatment response profile, complex dosing regimens offer advantages over fixed daily dosing regimens. Optimizing exposure to (or the plasma concentration-time profile of) the therapeutic agent by reducing the maintenance dose orAttorney Docket No. 130948.00011progressively increasing the interval between doses supports the transition to unmedicated self-regulation of emotion, behavior, and thought patterns. Maintenance dose adjustments such as a stepwise dose-reduction in dose over time may also mitigate potential rebound effects or relapses that are more likely to occur with abrupt discontinuation. Additionally, minimizing prolonged or unnecessary exposure to the therapeutic agent reduces the likelihood of dose -dependent adverse effects, thereby improving tolerability and enhancing overall treatment adherence.

[0154] In some embodiments, a dosing regimen for pharmacotherapy comprising a pharmaceutical preparation of bromantane is administered via an oral or oral mucosal route includes at least two distinct phases: an induction phase and a discontinuation phase. Tire induction phase of the dosing regimen is designed to efficiently achieve maximum therapeutic efficacy while minimizing the risk of side effects. The induction phase may involve a fixed daily dose of 25-150 mg / day for 3-14 days, or an initial loading dose of 50-300 mg on the first day of treatment, followed by a fixed daily dose of 25-150 mg / day for 2-13 days. The discontinuation phase of the dosing regimen, which immediately follows the induction phase, is designed to support a subject’s transition to an unmedicated state by systematically reducing exposure to the therapeutic agent in a manner that preserves therapeutic benefits, including extinction learning processes, and mitigates potential rebound effects to improve long-term treatment outcomes. The discontinuation phase has a defined duration ranging from 1 day to 2 months. The first dose of the discontinuation phase ranges from 10-150 mg and is equal to or lower than the last dose of the induction regimen. During the discontinuation phase, dose adjustments may be implemented in one or more of the following ways: progressively increasing the interval between doses, maintaining a lower fixed dose than that used in the induction phase, stepwise dose tapering, or a combination of these approaches. Additionally, placebo tablets containing 0 mg of the therapeutic agent may be administered on scheduled non-dosing days to improve adherence to the dosing regimen by enabling consistency in the dosing schedule. In an embodiment, the induction phase is related to adipose tissue distribution that can take a few days to normalize.

[0155] By way of example, a subject suffering from StUD is administered a pharmacotherapy to facilitate extinction learning, wherein the pharmacotherapy comprises a pharmaceutical preparation of bromantane formulated as oral tablets in various dose strengths to enable a complex dosing regimen over a 28-day treatment period. The tablets are arranged in a blister pack format with four rows of seven tablets in each row to provide a visual and practical adherence aid and ensure proper sequencing of administration throughout the 28-day treatment period. The dosing regimen involves administering one tablet per day, each tablet labeled according to the corresponding treatment day. The dosing regimen is structured with an induction phase followed by a discontinuation phase. The induction phase is the first week of treatment (Days 1-7),Attorney Docket No. 130948.00011beginning with an initial loading dose of 150 mg on Day 1. On Days 2-7, the subject receives a daily dose of 100 mg, completing the induction phase. The discontinuation phase is the next three weeks of treatment (Days 8-28). Beginning on Day 8, the corresponding tablet in the blister pack contains a placebo tablet with 0 mg of the therapeutic agent. The tablets corresponding to treatment days 9, 10. 11. 12, 13, and 14 contain 100, 0, 100, 0, 100, and 0 mg respectively to effectively increase the dosing interval to two days between doses of therapeutic agent during the second week of treatment. The discontinuation phase continues on Day 15 and is further modified by a step-wise decrease to 50 mg administered every two days for the third week of treatment (Days 15-21). In other words, tablets corresponding to treatment days 15, 16, 17, 18, 19, 20, and 21 contain 50, 0, 50, 0, 50, 0, and 50 mg of therapeutic agent respectively. For the final week of treatment, the doses in the discontinuation phase are step-wise decreased again to 25 mg administered every two days. In other words, tablets in the blister pack that correspond to treatment days 22, 23, 24, 25, 26, 27, and 28 contain 0, 25, 0, 25, 0, 25, and 0 mg of therapeutic agent respectively.

[0156] By way of example, a subject who has been prescribed a daily regimen of amphetamine by a medical professional does not meet the diagnostic criteria for StUD or Stimulant Withdrawal as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), but is scheduled to discontinue amphetamine therapy and is expected to experience stimulant withdrawal syndrome. The subject is prescribed a pharmacotherapy to alleviate withdrawal symptoms upon discontinuation of the amphetamine, wherein the pharmacotherapy comprises a pharmaceutical preparation of bromantane formulated as oral tablets, each containing 25 mg of the therapeutic agent, and a dosing regimen consisting of two distinct phases: an induction phase and a discontinuation phase. The total treatment duration is two weeks, with the induction phase consisting of fixed daily dosing at 50 mg / day for seven days, follow ed by the discontinuation phase with fixed daily dosing at 25 mg / day for the remaining seven days. The subject is instructed to swallow two 25 mg tablets every morning for the first seven days (50 mg / day) and then reduce the dose to one 25 mg tablet every morning (25 mg / day) for the final seven days of treatment.

[0157] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase fol low ed by a discontinuation phase, wherein the amount administered qd during the induction phase is greater than the amount administered qd during the discontinuation phase. In an embodiment, on a per day basis, the amount administered each day during the induction phase is greater than the amount administered each day during the discontinuation phase.

[0158] In an embodiment, (a) the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of (al) 100 mg qd for 3-14 days; (a2) 80 mg qd for 3-14 days; (a3) 50 mgAttorney Docket No. 130948.00011qd for 3-14 days; (a4) 40 mg qd for 3-14 days; (a5) 30 mg qd for 3-14 days; or (a4) 20 mg qd for 3-14 days; during tire induction phase; and wherein (b) the bromantane, analogue thereof, or a pharmaceutically acceptable salt thereof, is administered over a tapered schedule during the discontinuation phase. In an embodiment, a tapered schedule is a schedule in which each subsequent day has a lesser dose administered than the day before.

[0159] In another aspect of the disclosure, the disclosed pharmacotherapy facilitates the extinction of a maladaptive stimulus-response association, while an adaptive response to the same stimulus is established through cognitive and behavioral engagement. Newly formed adaptive associations can replace maladaptive associations involving the same stimulus, reinforcing lasting modifications in behaviors or thought patterns to reduce relapse vulnerability. A subject’s motivation to discontinue detrimental behaviors or thought patterns, awareness of the negative consequences of relapse, and ability to engage in future -oriented planning are examples of psychological determinants that correlate to therapeutic efficacy in the treatment of disorders of maladaptive learning. Adjunctive psychotherapy aimed at increasing the subject’s active participation in treatment can further strengthen these determinants by increasing motivation, reinforcing awareness of relapse triggers, and improving coping strategies for sustained recovery.

[0160] Nonlimiting examples of adjunctive psychotherapy that can integrated with pharmacotherapy to facilitate extinction learning and promote cognitive and behavioral engagement include: Structured Goal-Setting, Cognitive Restructuring, Cue-Exposure Therapy (CET), Motivational Interviewing (MI), Behavioral Activation Therapy, Implementation Intentions (If-Then Planning), Self-Monitoring and Reflection, Acceptance and Commitment Therapy (ACT), Contingency Management (CM), Cognitive Remediation Therapy, Mindfulness-Based Relapse Prevention (MBRP), Mental Contrasting with Implementation Intentions (MCII), Relapse Prevention Training, Exposure and Response Prevention (ERP), Prospective Memory Training. Behavioral Economic Training, Self-Affirmation Interventions, Habit Reversal Training (HRT), Interoceptive Exposure Therapy, Delayed Discounting Training.

[0161] In some embodiments, a subject presenting with symptoms of a mental disorder or syndrome undergoes a clinical assessment to determine whether one or more features of maladaptive learning contribute to. result from, or exacerbate their condition. A medical professional collaborates with the subject to develop a comprehensive treatment plan tailored to address the maladaptive responses identified as pivotal to the subject’s chief complaints. The comprehensive treatment plan comprises an interventional pharmacotherapy to facilitate the extinction of maladaptive emotions, behaviors, or thought patterns and an adjunctive psychotherapy component designed to reinforce adaptive responses. The pharmacotherapy comprises a pharmaceutical preparation of bromantane, formulated as a stabilized ASD for oral -mucosal administration inAttorney Docket No. 130948.00011the form of a sublingual film containing 50 mg of amorphous bromantane free base, which is administered each morning at a fixed dose of 50 mg / day for 28 days. Tire adjunctive psychotherapy is selected based on the subject’s clinical profile and may include cognitive restructuring, exposure therapy, behavioral activation, or other psychological interventions.

[0162] In an embodiment, the subject in need thereof is a pediatric male or female (i.e., 3 to 7 years old). In an embodiment, the subject in need thereof is an adolescent male or female (i.e., 8 to 12 years old). In an embodiment, the subject in need thereof is a teen male or female (i.e., 13-17 years old). In an embodiment, the subject in need thereof is an adult male or female (i.e., 18 to 64 years old). In an embodiment, the subject in need thereof is a geriatric male or female (i.e., 65 to 95 years old).

[0163] In an embodiment, disclosed herein is a method of modulating a receptor, tire method comprising facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, wherein the receptor is selected from cannabinoid receptor 2 (CB2), androgen receptor (AR), amylin receptor subtype 3 (AMY3), or orexin receptor 2 (0X2). In some embodiments, bromantane or an analogue of bromantane exhibits agonist activity at CB2. In some embodiments, bromantane or an analogue of bromantane exhibits antagonist activity at AR. In some embodiments, bromantane or an analogue of bromantane exhibits agonist activity at AMY3. In some embodiments, bromantane or an analogue of bromantane exhibits antagonist activity at OX2.

[0164] In an embodiment, disclosed herein is a method of modulating a network of receptors, the method comprising facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmacal preparation of bromantane, or an analogue of bromantane, wherein the receptors are selected from cannabinoid receptor 2 (CB2), androgen receptor (AR), amylin receptor subtype 3 (AMY3), orexin receptor 2 (0X2), or combinations thereof.

[0165] In an embodiment, disclosed herein is a method of creating a “network effect,” wherein bromantane, an analogue thereof, modulates multiple receptor types for which the compound exhibits measurable activity in the micromolar range, and wherein the combined modulation produces a cumulative therapeutic effect that facilitates extinction learning in a subject in need thereof. In some embodiments, the cumulative therapeutic effect is greater than would be expected from the sum of the effects attributable to modulation of the individual receptors at comparable micromolar activity levels. In some embodiments, without being bound by any particular theory’, the network effect arises from concurrent modulation of multiple protein targets, including through direct and / or indirect interactions, each exhibiting relatively low individual potency, which produces a cumulative therapeutic effect that facilitates extinction learning in a subject in need thereof.Attorney Docket No. 130948.00011

[0166] In some embodiments, and without being bound by theory, bromantane or an analogue thereof exerts one or more cellular effects through bilayer mediated modulation of membrane protein function. As demonstrated by the gramicidin-based fluorescence assay described herein, bromantane partitions into lipid bilayers and produces concentration-dependent changes in aggregate bilayer material properties, as reflected by measured NormRate values and the derived bilayer deformation energy perturbation, AAGdef = -kBT ln(NormRate). Changes in bilayer physical properties can alter the energetic cost of transmembrane conformational transitions, including by shifting local bilayer thickness, elasticity, compressibility, curvature stress, and tire lateral pressure profde. In this manner, bromantane induced changes in the membrane environment can propagate as network effects across a subset of membrane embedded proteins that are comparatively susceptible to bilayer mechanics, including in some embodiments G protein -coupled receptors (GPCRs) and GPCR complexes. Consistent with this mechanism, the concentration dependence of bromantane’s bilayer perturbation (e.g., [FTG. 29], [FIG. 30], [FIG. 31]) can be correlated with concentration dependent functional modulation observed in cell based assays for susceptible receptors, including but not limited to cannabinoid receptor 2 (CB2) (e.g., [FIG.32], [FIG 33]), androgen receptor (AR) (e.g., [FIG. 34]), amylin receptor subtype 3 (AMY3) (e g., [FIG. 35]), and orexin receptor 2 (0X2) (e.g., [FIG. 36]). Uris correlation supports the conclusion that bromantane can indirectly modulate receptor signaling by changing the membrane energetic landscape that governs receptor conformational equilibria, coupling efficiency, and / or trafficking.

[0167] In some embodiments, bilayer mediated modulation of membrane protein function is selective rather than indiscriminate. Different classes of membrane proteins are expected to exhibit different sensitivities to bilayer perturbations because their functional transitions and regulatory interactions differ in the extent to which they are coupled to bilayer deformation energetics versus other determinants such as specific lipid binding, cytoskeletal anchoring, or strong protein-protein interactions. For example, certain transporters, including SLC6 family proteins, may display comparatively reduced functional modulation under conditions where GPCRs are measurably affected, which may occur when transporter activity is dominated by mechanisms less dependent on the bilayer deformation term captured by the gramicidin reporter, or when compensatory stabilizing interactions reduce susceptibility to changes in bilayer mechanics. Accordingly, the observed pattern in which bromantane modulates multiple GPCR targets while exhibiting lesser effects on SLC6 proteins is unexpected and supports embodiments in which bromantane produces coordinated, membrane-mediated network effects among susceptible membrane proteins, while leaving other membrane proteins comparatively less affected.Attorney Docket No. 130948.00011

[0168] In some embodiments, empirical screening of bromantane across a large assay panel evaluating diverse protein targets identified a comparatively small subset of susceptible membrane protein targets, indicating that protein target susceptibility to membrane-mediated effects described herein is selective and not readily predictable. In some embodiments, the susceptible subset includes targets not conventionally implicated as direct modulators of monoaminergic neurotransmission, thereby supporting the unexpected nature of the observed target-response pattern and the network effects described herein. In some embodiments, bromantane analogues described herein may exhibit similar selective membrane-mediated target susceptibility patterns and corresponding network effects.

[0169] In some embodiments, agonist activity at the cannabinoid receptor 2 (CB2) is relevant to the treatment of disorders of maladaptive learning, including addiction, because CB2 signaling can modulate neurobehavioral processes that influence motivated behavior, cue reactivity, and relapse relevant responding, and CB2 has also been described to regulate neuroimmune and microglial pathways that can affect neural circuit function. CB2 ligands are known to exhibit pathway dependent signaling profiles. Arrestin recruitment assays provide a functional measure of CB2 engagement that can complement other CB2 signaling readouts. Without being bound by any particular theory, by reducing the reinforcing impact or incentive salience of conditioned stimuli, including drug associated cues, and by promoting neurophysiological states that favor adaptive updating of learned associations, CB2 agonism may support extinction learning during cue exposure or other extinction-based interventions. Accordingly, compounds that exhibit CB2 agonist activity can be used, alone or in combination with behavioral therapy, to facilitate extinction learning and reduce relapse liability in subjects affected by addiction or other disorders of maladaptive learning.

[0170] In some embodiments, modulation of the androgen receptor (AR), a ligand activated nuclear hormone receptor that regulates transcriptional programs following ligand binding, is relevant to the treatment of disorders of maladaptive learning, including addiction, because androgen signaling has been described to influence central nervous system circuits that regulate motivated behavior and reinforcement processing. AR related signaling has been reported to modulate mesocorticolimbic pathways and dopamine associated behavioral outputs that contribute to cue reactivity and relapse relevant responding. Without being bound by any particular theory, a compound that binds AR and functionally reduces AR activation, for example by inhibiting agonist driven AR nuclear translocation in a cell based assay, may reduce the incentive salience or reinforcing impact of conditioned stimuli, including drug associated cues, thereby decreasing cue evoked responding and promoting conditions that favor updating of conditioned associations during cue exposure or other extinction based interventions. Accordingly, compounds exhibiting functional antagonism can be used,Attorney Docket No. 130948.00011alone or in combination with behavioral therapy, to facilitate extinction learning and reduce relapse liability in subjects affected by addiction or other disorders of maladaptive learning.

[0171] In some embodiments, agonist activity at the AMY3 receptor, a heteromeric amylin receptor complex comprising the calcitonin receptor (CALCR) and receptor activity modifying protein 3 (RAMP3), is relevant to the treatment of disorders of maladaptive learning, including addiction, because AMY3 is a Gs coupled receptor that signals through increases in intracellular cAMP and is expressed in the central nervous system, where amylin receptor signaling has been described in neural circuits involved in motivated behavior and cue responsiveness. Pharmacological engagement of amylin receptor pathways has been reported to modulate reward related behaviors in preclinical models, including attenuation of alcohol related intake and related measures of reinforcement. Without being bound by any particular theory, activation of AMY3 signaling may reduce the reinforcing impact or incentive salience of conditioned stimuli, including drug associated cues, thereby decreasing cue evoked responding and creating conditions that favor updating of conditioned associations during cue exposure or other extinction based interventions. Accordingly, a compound exhibiting AMY3 agonist activity can be used, alone or in combination with behavioral therapy, to facilitate extinction learning and reduce relapse liability in subjects affected by addiction or other disorders of maladaptive learning.

[0172] In some embodiments, functional antagonism of the orexin receptor 2 (0X2) is relevant to the treatment of disorders of maladaptive learning, including addiction, because orexin signaling is implicated in neurobehavioral processes that regulate arousal, motivated behavior, and cue reactivity, each of which can contribute to relapse vulnerability. 0X2 is a G protein coupled receptor that can engage intracellular signaling pathways that include calcium mobilization, and an in vitro 0X2 antagonist calcium flux assay provides a functional measure of inhibition of orexin driven calcium signaling. Selective 0X2 receptor antagonism has been reported to attenuate cue-induced reinstatement in certain preclinical relapse paradigms, consistent with a role for 0X2 signaling in conditioned cue responsiveness. Without being bound by any particular theory, by reducing cue evoked arousal or motivational drive and decreasing the behavioral impact of conditioned stimuli such as drug associated cues, 0X2 antagonism may promote conditions that support updating of conditioned associations during cue exposure or other extinction based interventions, thereby facilitating extinction learning and reducing relapse liability in subjects affected by addiction or other disorders of maladaptive learning.

[0173] In some embodiments, and without being bound by theory, the method disclosed herein operates on a lipid membrane model of adaptive response, wherein administration of bromantanc, an analogue thereof, or a pharmacally acceptable salt thereof results in partitioning of the compound into lipid membranes and, asAttorney Docket No. 130948.00011a consequence, indirect modulation of one or more membrane associated proteins or networks of membrane associated proteins. In some embodiments, the compound is administered according to a complex dosing regimen comprising an induction phase followed by a discontinuation phase. During the induction phase, bromantane. an analogue thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in one or more doses and dosing intervals selected to achieve the membrane -mediated pharmacological effects described herein. Compound concentrations in lipid bilayers, lipid-rich tissues, or membrane-associated microenvironments may be measured directly or estimated based on pharmacokinetic modeling (e.g., partitioning models, tissue distribution models, physiologically based pharmacokinetic models) or based on pharmacodynamic response patterns (e g., effect-time profdes, persistence of effect after dose reduction or dose interruption, concentration-effect hysteresis, biomarker response profiles). Following the induction phase, the discontinuation phase comprises continued administration at a dose and dosing interval selected to maintain the therapeutic effects while reducing total compound exposure relative to the induction phase.Embodiments

[0174] In an embodiment, disclosed herein, is a method of treating a disorder of maladaptive learning in a subject in need thereof, the method includes facilitating extinction learning in the subject in need thereof by administering a therapeutically effective amount of a pharmacal preparation of bromantane, or an analogue of bromantane, to the subject in need thereof.

[0175] In an embodiment, the therapeutically effective amount is a dose ranging from 10 mg to 200 mg per day.

[0176] In an embodiment, the therapeutically effective amount is administered only once per day and without any administering a secondary therapeutic agent.

[0177] In an embodiment, the therapeutically effective amount is 50 mg and administered orally once a day for 7 days.

[0178] In an embodiment, the therapeutically effective amount is a dose ranging from 50 mg to 100 mg per day, wherein the administering is carried out over a treatment period of 1 week to 6 weeks.

[0179] In an embodiment, the disorder of maladaptive learning is a drug withdrawal syndrome.

[0180] In an embodiment, the drug withdrawal syndrome is a stimulate withdrawal syndrome disorder.Attorney Docket No. 130948.00011

[0181] In an embodiment, the disorder of maladaptive learning is a substance use disorder.

[0182] In an embodiment, the substance use disorder is stimulant use disorder.

[0183] In an embodiment, the disorder of maladaptive learning is oppositional defiant disorder, intermittent explosive disorder, kleptomania, pyromania, post-traumatic stress disorder, acute stress disorder, complex post-traumatic stress disorder, adjustment disorders, generalized anxiety disorder, panic disorder, social anxiety disorder, phobias, obsessive-compulsive disorder, major depressive disorder, persistent depressive disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, orthorexia nervosa, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, somatic symptom disorder, illness anxiety disorder, conversion disorder, depersonalization-derealization disorder, dissociative identity disorder, or combinations thereof.

[0184] In an embodiment, bromantane, or the analogue of bromantane, has a chemical structure according to Formula I,wherein an adamantane ring system (A) is covalently linked to a phenyl ring (B) by a linker (L); Ri, R2, and Rs are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl: R4. R5, and Re are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5-member ring, wherein the fused 5-member ring is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane; L is independently selected from amine, amide, or imine.

[0185] In an embodiment, the L is amine.

[0186] In an embodiment, the L is amide.

[0187] In an embodiment, the L is imine.Attorney Docket No. 130948.00011

[0188] In an embodiment, the at least one of Ri, R2, and Rs is fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl.

[0189] In an embodiment, the pharmaceutical preparation is in the form of a tablet.

[0190] In an embodiment, the pharmaceutical preparation comprises one or more pharmacally acceptable excipients that inhibits crystallization.

[0191] In an embodiment, the bromantane, or the analogue of bromantane, is amorphous.

[0192] In an embodiment, the method further comprising prior to administering the therapeutically effective amount, assessing a subject suffering from symptoms of a mental disorder or syndrome to detennine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms.

[0193] In an embodiment, the analogue of bromantane is selected from constitutional isomers, stereoisomers, isotopes, prodrugs, metabolites, precursors, or derivatives of bromantane.

[0194] In an embodiment, the analogue of bromantane is constitutional isomers selected from tautomers, regioisomers, skeletal isomers, functional group isomers, metamers, ring -chain isomers, or combinations thereof.

[0195] In an embodiment, the analogue of bromantane is stereoisomers selected from geometric isomers, enantiomers, diastereomers, conformational isomers, or combinations thereof.

[0196] In an embodiment, the bromantane, or the analogue of bromantane, is an amorphous free base.

[0197] In an embodiment, the pharmaceutical preparation is a tablet containing 20 mg of stabilized amorphous bromantane.

[0198] In an embodiment, the pharmaceutical preparation is a tablet containing 22.4 mg of crystalline bromantane hydrochloride salt.

[0199] In an embodiment, disclosed herein, is a method of treating a disorder of maladaptive learning, the method comprising assessing a subject in need thereof suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms: and facilitating extinction learning in the subject in need thereof by administering a therapeutically effective amount of a pharmaceutical preparation of bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, to the subject in need thereof.Attorney Docket No. 130948.00011

[0200] In an embodiment, the method facilitates extinction learning in the subject.

[0201] In an embodiment, the subject in need thereof suffers from the disorder of maladaptive learning and optionally a disorder selected from oppositional defiant disorder, intermittent explosive disorder, kleptomania, pyromania, post-traumatic stress disorder, acute stress disorder, complex post -traumatic stress disorder, adjustment disorders, generalized anxiety disorder, panic disorder, social anxiety disorder, phobias, obsessive-compulsive disorder, major depressive disorder, persistent depressive disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, orthorexia nervosa, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, somatic symptom disorder, illness anxiety disorder, conversion disorder, depersonalization-derealization disorder, dissociative identity disorder, or combinations thereof.

[0202] In an embodiment, the subject in need thereof suffers from the disorder of maladaptive learning and optionally a syndrome selected from substance withdrawal syndrome, stress-related syndrome, trauma-related syndrome, anxiety-related syndrome, circadian rhythm-related syndrome, mood-related syndrome, somatization syndrome, impulse control syndrome, or combinations thereof.

[0203] In an embodiment, the syndrome is a substance withdrawal syndrome.

[0204] In an embodiment, the substance withdrawal syndrome is stimulant withdrawal.

[0205] In an embodiment, the disorder of maladaptive learning is a substance use disorder.

[0206] In an embodiment, the substance use disorder is stimulant use disorder.

[0207] In an embodiment, the substance is selected from antidepressants, anxiolytics, antipsychotics, stimulants, and pain medications.

[0208] In an embodiment, disclosed herein, is a method of treating stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof.

[0209] In an embodiment, the stimulant use disorder or stimulant withdrawal is influenced by maladaptive learning.

[0210] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered as a single-agent therapeutic.Attorney Docket No. 130948.00011

[0211] In an embodiment, the therapeutically effective amount is administered only once per day and without any administering of a secondary therapeutic agent.

[0212] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 7 days.

[0213] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 14 days.

[0214] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 21 days.

[0215] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 7 days.

[0216] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 14 days.

[0217] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 21 days.

[0218] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 7 days.

[0219] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase.

[0220] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase, wherein the amount administered qd during the induction phase is greater than the amount administered qd during the discontinuation phase.

[0221] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days.Attorney Docket No. 130948.00011

[0222] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days during the discontinuation phase.

[0223] In an embodiment, the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 3-14 days during the induction phase and administered in a dose of 40 mg qd for 1-60 days during the discontinuation phase.

[0224] In an embodiment, (a) the bromantane, the analogue thereof, or a pharmaceutically acceptable salt thereof, is administered in a dose of (al) 100 mg qd for 3-14 days; (a2) 80 mg qd for 3-14 days; (a3) 50 mg qd for 3-14 days; (a4) 40 mg qd for 3-14 days; (a5) 30 mg qd for 3-14 days; or (a4) 20 mg qd for 3-14 days; during tire induction phase; and wherein (b) the bromantane, analogue thereof, or a pharmaceutically acceptable salt thereof, is administered over a tapered schedule during the discontinuation phase.

[0225] In an embodiment, the administering an adjunctive psychotherapy to the subject in need thereof, wherein the adjunctive psychotherapy facilitates the development of adaptive responses in the subject.

[0226] In an embodiment, prior to administering the therapeutically effective amount, assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms.

[0227] In an embodiment, the subject in need thereof is a pediatric male or female.

[0228] In an embodiment, the subject in need thereof is an adolescent male or female.

[0229] In an embodiment, the subject in need thereof is a teen male or female.

[0230] In an embodiment, the subject in need thereof are administered or have been administered attention-deficit / hyperactivity disorder (ADHD) medications.

[0231] In an embodiment, the ADHD medication is Ritalin, Adderall, or combinations thereof.

[0232] In an embodiment, disclosed herein, is a method of treating a disorder of maladaptive learning, the method comprising assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; and facilitating extinction learning in the subject in need thereof by administering to theAttorney Docket No. 130948.00011subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);R1, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, R5, and R6, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane);L is independently selected from amine, amide, or imine; andthe chemical structure differs in at least one substituent (Rl, R2, R3, R4, R5, R6, or L) such that it is structurally distinct from bromantane.

[0233] In an embodiment, disclosed herein, is a method of treating a disorder of maladaptive learning, the method comprising facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,Attorney Docket No. 130948.00011or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Rl, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, R5, and R6, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane);L is independently selected from amine, amide, or imine.

[0234] In an embodiment, disclosed herein, is a method of treating a disorder of maladaptive learning, the method comprising facilitating extinction learning in the subject in need thereof by administering to tire subject an effective amount of a pharmaceutical preparation of an analogue of bromantane, having a chemical structure according to Formula I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Ri, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, Rs, and Re, arc substituents on B that arc independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane);L is independently selected from amine, amide, or imine; andAttorney Docket No. 130948.00011the chemical structure differs in at least one substituent (Ri, Ri, Rs, R4, Rs, Re, or L) such that it is structurally distinct from bromantane.

[0235] In an embodiment, disclosed herein, is a method of modulating a network of receptors, the method comprising facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, wherein the receptors arc selected from cannabinoid receptor 2 (CB2), androgen receptor (AR), amylin receptor subtype 3 (AMY3), orexin receptor 2 (0X2), or combinations thereof.

[0236] In an embodiment, the method comprises administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to agonize the CB2 receptor.

[0237] In an embodiment, the method comprises administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to antagonize the AR receptor.

[0238] In an embodiment, the method comprises administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to agonize the AMY3 receptor.

[0239] In an embodiment, the method comprises administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to antagonize the 0X2 receptor.

[0240] In an embodiment, the method comprises administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to agonize the CB2 receptor, to antagonize the AR receptor, to agonize the AMY3 receptor, and to antagonize the 0X2 receptor. In an embodiment, disclosed herein, is a pharmaceutical preparation comprising a therapeutically effective amount of bromantane as a drug substance in the form of a salt, solvate, complex, or conjugate; and one or more pharmacally acceptable excipients that inhibit crystallization, wherein, the morphology of the drug substance is amorphous.

[0241] In an embodiment, disclosed herein, is a pharmaceutical preparation comprising a therapeutically effective amount of bromantane in amorphous free base form: and one or more pharmaceutically acceptable excipients.Attorney Docket No. 130948.00011

[0242] In an embodiment, the bromantane is present in an amorphous solid dispersion.

[0243] In an embodiment, the pharmaceutically acceptable excipient that functions to inhibit crystallization contains a functional group selected from the group consisting of sulfate, phosphate, and carboxylate.

[0244] In an embodiment, the pharmaceutically acceptable excipient that inhibits crystallization contains a carboxylate.

[0245] In an embodiment, the pharmaceutical preparation is a tablet dosage form comprising 20mg to 200 mg of an amorphous solid dispersion of bromantane in copovidone, wherein bromantane is present in the Amorphous Solid Dispersion at 30 to 80 %w / w.

[0246] In an embodiment, the pharmaceutical preparation is an oral thin film comprising: 20 mg to 80 mg of amorphous bromantane and 20mg to 150 mg of pullulan.

[0247] In an embodiment, disclosed herein, is a method of treating a comorbidity associated with stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, or an analogue of bromantane, or a pharmaceutically acceptable salt thereof.

[0248] In an embodiment, the comorbidity is attention deficit hyperactivity disorder (ADHD).

[0249] In an embodiment, the comorbidity is a stress -related syndrome.

[0250] In an embodiment, the comorbidity is selected from anxiety, depression, personality disorders, or combinations thereof.

[0251] In an embodiment, disclosed herein, is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof.

[0252] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein said stimulant use disorder or stimulant withdrawal is influenced by maladaptive learning.Attorney Docket No. 130948.00011

[0253] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered as a single-agent therapeutic.

[0254] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the therapeutically effective amount is administered only once per day and without any administering of a secondary therapeutic agent.

[0255] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 7 days.

[0256] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 50 mg qd for 14 days.

[0257] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 50 mg qd for 21 days.

[0258] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 80 mg qd for 7 days.

[0259] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 80 mg qd for 14 days.

[0260] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 80 mg qd for 21 days.

[0261] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 100 mg qd for 7 days.Attorney Docket No. 130948.00011

[0262] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase.

[0263] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase, wherein the amount administered qd during the induction phase is greater than the amount administered qd during the discontinuation phase.

[0264] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days.

[0265] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days during the discontinuation phase.

[0266] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of 80 mg qd for 3-14 days during the induction phase and administered in a dose of 40 mg qd for 1-60 days during the discontinuation phase.

[0267] In an embodiment, disclosed herein is bromantane, an analogue thereof, or a pharmacally acceptable salt thereof, for use in the treatment of stimulant use disorder or stimulant withdrawal in a subject in need thereof, administered in a dose of (al) 100 mg qd for 3-14 days; (a2) 80 mg qd for 3-14 days; (a3) 50 mg qd for 3-14 days; (a4) 40 mg qd for 3-14 days; (a5) 30 mg qd for 3-14 days; or (a4) 20 mg qd for 3-14 days; during the induction phase; and wherein (b) the bromantane, analogue thereof, or the pharmaceutically acceptable salt thereof, is administered over a tapered schedule during the discontinuation phase .

[0268] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to theAttorney Docket No. 130948.00011subject a therapeutically effective amount of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof.

[0269] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein said stimulant use disorder or stimulant withdrawal is influenced by maladaptive learning.

[0270] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered as a single-agent therapeutic.

[0271] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, the therapeutically effective amount is administered only once per day and without any administering of a secondary therapeutic agent.

[0272] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmacally acceptable salt thereof, is administered in a dose of 50 mg qd for 7 days.

[0273] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 14 days.

[0274] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 21 days.

[0275] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant useAttorney Docket No. 130948.00011disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 7 days.

[0276] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 14 days.

[0277] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 21 days.

[0278] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmacally acceptable salt thereof, is administered in a dose of 100 mg qd for 7 days.

[0279] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmacally acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase.

[0280] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase, wherein the amount administered qd during the induction phase is greater than the amount administered qd during the discontinuation phase.

[0281] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days.Attorney Docket No. 130948.00011

[0282] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days during the discontinuation phase.

[0283] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmacally acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 3-14 days during the induction phase and administered in a dose of 40 mg qd for 1-60 days during the discontinuation phase.

[0284] In an embodiment, disclosed herein is the use of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a stimulant use disorder or stimulant withdrawal in a subject in need thereof, wherein (a) the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of (al) 100 mg qd for 3-14 days; (a2) 80 mg qd for 3-14 days; (a3) 50 mg qd for 3-14 days; (a4) 40 mg qd for 3-14 days; (a5) 30 mg qd for 3-14 days; or (a4) 20 mg qd for 3-14 days; during the induction phase; and wherein (b) the bromantane, analogue thereof, or the pharmaceutically acceptable salt thereof, is administered over a tapered schedule during the discontinuation phase.EXAMPLES

[0285] Example 1: Lipid bilayer GFA Assay

[0286] A gramicidin-based fluorescence assay (GFA) was used to quantify bromantane induced perturbations of lipid bilayer physical properties by exploiting the well characterized gramicidin monomer / dimer equilibrium that underlies formation of functional gramicidin channels. Gramicidin was incorporated into lipid bilayers of liposomes and the fluorescence-based readout was configured such that the measured reporter rate reflected gramicidin channel formation and therefore the free-energy balance governing gramicidin dimerization in the membrane. Test compound solutions of bromantane were applied over a concentration range of 0.0005 pM to 10 pM. and a normalized rate (NormRate) was determined at each concentration relative to a vehicle control. Compounds that partition into the bilayer and alter bilayer material properties (including, for example, bilayer thickness, elasticity, compressibility, and the lateral pressure profile) change the bilayer deformation energy term (AGdef) associated with gramicidin dimerization, thereby shifting the channel forming equilibrium and producing a corresponding change in NormRate. NormRateAttorney Docket No. 130948.00011values were converted to a bilayer deformation energy perturbation according to the relationship AAGdef = -kBT ln(NormRate), where kB is the Boltzmann constant, T is absolute temperature, and kBT = 2.478 kJ / mol at 25 °C. Hie concentration-dependent NonnRate and derived AAGdef values were used to characterize the magnitude and direction of bromantane ’s bilayer-mediated mechanical effects across the tested concentration range.

[0287] Bromantanc exhibited concentration dependent biphasic effects on cell membrane (lipid bilaycr) physical properties ([FIG.29], [FIG. 30], and [FIG. 31]). At high concentrations (>0.37 pM), the compound induced membrane stiffening (NormRate <1), characterized by decreased gramicidin channel activity. At low concentrations (<0.12 pM), it induced membrane softening (NormRate >1), characterized by increased channel activity. This biphasic pattern reflects concentration-dependent alterations in bilayer elasticity, thickness, and curvature.

[0288] Example 2: AR, CB1, and CB2 Radioligand Competition Binding Assays

[0289] Bromantane interactions with human androgen receptor (AR), cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2) were evaluated in vitro using radioligand competition binding assays. In each assay, bromantane was incubated with a receptor preparation and a fixed concentration of radiolabeled ligand. Binding measured in the presence of bromantane was compared with vehicle control binding to determine inhibition of control binding. Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in duplicate at a final concentration of 10 pM. For each run, specific binding was defined as total binding minus non-specific binding. Control specific binding was the specific binding measured in vehicle control wells. Results for bromantane were expressed as % Inhibition of Control Specific Binding = 100 - % Control Specific Binding, where % Control Specific Binding = (Measured Specific Binding / Control Specific Binding) x 100.

[0290] For the AR radioligand competition binding assay, receptor preparations were incubated with the agonist radioligand [3H]methyltrienolone at 1 nM (radioligand Kd = 0.6 nM). Non-specific binding was determined in the presence of testosterone at 1 pM. Incubations were perfonned for 240 minutes at 22°C, and bound radioactivity was quantified by scintillation counting.

[0291] For the CB1 radioligand competition binding assay, receptor preparations were incubated with the agonist radioligand [3H]CP 55940 at 2 nM (radioligand Kd = 0.9 nM). Non-specific binding was determined in the presence of AM281 at 10 pM. Incubations were performed for 30 minutes at 22°C, and bound radioactivity was quantified by scintillation counting.Attorney Docket No. 130948.00011

[0292] For the CB2 radioligand competition binding assay, receptor preparations were incubated with the agonist radioligand [3H]WIN 55212-2 at 0.8 nM (radioligand Kd = 1.5 nM). Non-specific binding was determined in the presence of using WIN 55212-2 at 5 pM. Incubations were performed for 120 minutes at 37°C, and bound radioactivity was quantified by scintillation counting.

[0293] Bromantane (10 pM; duplicate determinations) produced negligible inhibition of [3H]CP 55940 specific binding at CB1 (mean = 6.4% inhibition), moderate inhibition of [3H]WIN 55212-2 specific binding at CB2 (mean = 47.2% inhibition), and moderate inhibition of [3H]methyltrienolone specific binding at AR (mean = 76.5% inhibition). A mean of 6.4% inhibition is essentially no inhibition of CP 55940 binding at CB1 by bromantane and demonstrates that bromantane is selective for the CB2 receptor subtype compared to CB1.

[0294] Example 3: CB1 and CB2 Cell Based P-Arrestin Recruitment Assays

[0295] Bromantane interactions with human cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) were evaluated in vitro using cell based P-arrestin recruitment assays. The assays use CH0-K1 cells expressing CB1 or CB2 fused to an enzyme donor fragment and P-arrestin fused to an enzyme acceptor fragment. Upon receptor activation, p-arrestin is recruited to the receptor, which drives enzyme fragment complementation and enzymatic cleavage of a detection reagent to generate a chemiluminescent signal proportional to P-arrestin recruitment, measured as relative light units (RLU). Assays were conducted in well plates with cells plated in a final volume of 20 pL per well and incubated at 37°C prior to compound addition.

[0296] Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in duplicate at a final concentration of 1.0 LIM. with vehicle concentration held constant at 1% final DMSO. For agonist mode, compounds were incubated with cells for 120 minutes at 37°C. For antagonist mode, compounds were added to cells and then challenged with an ECso concentration of the reference agonist, followed by a 2 hour incubation at 37°C. Tire reference agonist used to define maximal activation and to generate ECso challenge conditions was CP55940 for both CB1 and CB2. Antagonist assay controls included inhibitors AM281 for CB1 and JTE 907 for CB2 to verify inhibition under agonist challenge conditions. Following incubation, chemiluminescent detection reagent was added to each well, plates were incubated for 1 hour at room temperature, and luminescence was read on a plate reader. For agonist mode, results were expressed as percent activity relative to the baseline (vehicle) and maximum response control: % Activity = [(Mean RLUtest - Mean RLUvehicle) / (Mean RLUmax control - Mean RLUvehicle)] * 100. For antagonist mode, results were expressed as percent inhibition relative to baseline and EC80 agonist challenge control: %Attorney Docket No. 130948.00011Inhibition = [1 - (Mean RLUtest - Mean RLUvehicle) / (Mean RLU EC80 control — Mean RLUvehicle)] x 100.

[0297] In agonist mode, observed activity >30% with RLS signals statistically different than baseline was considered to indicate significant interaction in which the test compound was acting as an agonist to activate the receptor and induce arrestin recruitment. In agonist mode, observed inhibition >50% with RLS signals statistically different than the EC80 control was considered to indicate significant interaction in which the test compound was acting as an acting as an antagonist to inhibit receptor activation and arrestin recruitment. Bromantane (1.0 pM; duplicate determinations) produced RLU signals corresponding to 2.8% activity in agonist mode for CB1, 7.6% inhibition in antagonist mode for CBL 32.4% activity in agonist mode for CB2, and 10.8% inhibition in antagonist mode for CB2. The agonist effect at CB2R was further characterized using a concentration-response curve spanning ten concentrations (from X to Y). An ECso value of 0.11 pM was determined by nonlinear regression analysis of the dose-response data with max response = 45% of control [FIG. 32],

[0298] Example 4: CB1 and CB2 Cell Based cAMP Assays

[0299] Bromantane interactions with human cannabinoid receptor 1 (CB 1) and cannabinoid receptor 2 (CB2) were evaluated in vitro using CB1 and CB2 expressing cAMP reporter cell lines in both agonist and antagonist modes. Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in 10-point concentration response format over a final assay concentration range of 0.0005 to 10 pM in assay buffer. Cell line stock suspensions were prepared at lOx cell concentration in assay buffer and seeded into well plates to a target a final cell concentration of lx for the assays. Intracellular cAMP was quantified using an enzyme donor cAMP reagent (ED-cAMP) and enzyme fragment complementation detection (EFC) with [3-galactosidase as the functional endpoint. Chemiluminescent signal was read as relative light units (RLU) and was proportional to endogenous cAMP levels.

[0300] Because CB 1 and CB2 are Gi coupled receptors, agonist mode measured receptor activation as inhibition of NKH 477 stimulated cAMP production. Cells were incubated with ED-cAMP reagent in the presence of NKH 477, then exposed to bromantane (serial dilutions) to generate concentration response curves. Antagonist mode measured blockade of receptor signaling by challenging cells with a reference agonist at an EC80 concentration in the presence of bromantane. Cells were preincubated w ith bromantane (serial dilutions) and then exposed to the ECso agonist challenge to quantify reversal of the agonist mediated inhibition of cAMP production. The reference agonist used to define maximal activation and ECso challengeAttorney Docket No. 130948.00011conditions was CP55940 for CB1 and CB2. Assay performance was verified by laboratory reference controls AM251 (CB1 antagonist control) and SR144528 (CB2 antagonist control).

[0301] For Gi coupled receptors in agonist mode, results were expressed as percent activity relative to baseline and maximum response controls using the relationship: % Activity = 100 x [1 - (Mean RLUtest -Mean RLUmax control) / (Mean RLUvehicle - Mean RLUmax control)] . For Gi coupled receptors in antagonist mode, results were expressed as percent inhibition relative to baseline and ECso agonist challenge control using: % Inhibition = 100 x (RLUtest - Mean RLUvehicle) / (Mean RLUmax control — Mean RLUvehicle), where RLUtest is measured in the presence of test compound plus EC80 agonist, and RLUvehicle is measured in the presence of vehicle plus ECso agonist. At the highest concentration tested (10 pM), bromantane produced RLU signals corresponding to 25% activity in agonist mode for CB1, 2.3% inhibition in antagonist mode for CB1, 38% activity in agonist mode for CB2 [FIG. 33], and 4.3% inhibition in antagonist mode for CB2.

[0302] Example 5: AR Cell Based Nuclear Translocation Assays

[0303] Bromantane was evaluated for activity at the human androgen receptor (AR) using cell based nuclear translocation assays run in both agonist and antagonist modes. Ligand dependent AR nuclear translocation was quantified in an engineered reporter cell system with signal detected as chemiluminescence (relative light units, RLU). Cells were expanded in cell seeding media, cultured in flasks, and then maintained overnight in starvation media containing 0.1% serum and 10% charcoal dextran stripped serum. After which, cells were resuspended in assay media containing 10% serum replacement and seeded at 30 pL per well into well plates. Plates were incubated at 37°C.

[0304] Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in duplicate in 10-point concentration response format over a final assay concentration range of 0.0005 to 10 pM in assay buffer. In agonist mode, bromantane serial dilutions were prepared at lOx in assay media and added to cells at 5 pL per well, followed by incubation for 5 hours at 37°C. In antagonist mode, bromantane was prepared at 5x in assay media and added at 5 pL per well, followed by preincubation for 1 hour at 37°C. Antagonist determination was then initiated by adding 5 pL per well of a 7x EC80 concentration of an AR agonist challenge, followed by incubation for 4 hours at 37°C. The reference agonist was BMS-564929 and reference antagonist was geldanamycin. After compound incubation (and agonist challenge for antagonist mode), detection reagent solution was added at 20 pL per well and incubated for 1 hour at room temperature.Luminescence was then read on a plate reader. Concentration response curves were fit by nonlinear regression to determine EC50 in agonist mode or IC50 in antagonist mode.Attorney Docket No. 130948.00011

[0305] In the AR agonist nuclear translocation assay, bromantane showed no measurable agonist activity across the tested concentration range, with EC50 > 10 pM and maximal response = 0%. In the AR antagonist nuclear translocation assay, bromantane inhibited agonist driven AR nuclear translocation with apparent IC50 = 2.6 pM (Hill slope = 1.23. curve bottom and top constrained to 0% and 100%, and maximal response = 82% at the highest concentration tested 10 pM), [FIG. 34] . A high-concentration plateau was not fully established at the top dose.

[0306] Example 6: OXI and OX2 Cell Based Calcium Flux Assays

[0307] Bromantane interactions with human orexin receptor 1 (OXI) and orexin receptor 2 (OX2) were evaluated in vitro using CH0-K1 cell lines expressing the respective human receptors and a real time calcium mobilization readout based on dye fluorescence. The assays were performed in both agonist and antagonist modes. Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in duplicate in 10-point concentration response format over a final assay concentration range of 0.0005 to 10 pM in assay buffer. Cells were seeded in poly-D-lysine coated well plates (20 pL per well) and incubated at 37°C.Growth medium was then removed and cells were dye loaded with 20 pL per well of dye loading buffer containing detection reagent and probenecid in assay buffer (30-60 min, 37°C). Calcium flux baseline was measured followed by a kinetic read after reagent addition.

[0308] In agonist mode, bromantane was added (10 pL per well) and calcium flux was recorded. Data were expressed as percent activity relative to vehicle and the control activator (Orexin A). In antagonist mode, bromantane was preincubated (10 pL per well,) followed by addition of Orexin A at an ECso challenge concentration (10 pL per well). Calcium flux was recorded and data were expressed as percent inhibition relative to vehicle and the EC80 control ligand condition. Concentration response curves were fit by nonlinear regression to determine EC50 in agonist mode or 1C50 in antagonist mode.

[0309] Bromantane showed no agonist activity up to the maximum concentration tested (10 pM) at OXI or OX2 based on calcium flux measurements, EC50 > 10 pM and maximal response 0%. In the presence of an Orexin A ECso challenge (antagonist mode), inhibition of OXI mediated calcium flux by bromantane over the tested range was minor, IC50 > 10 pM and maximal response 12%. In the antagonist mode, bromantane inhibited OX2 mediated calcium flux at apparent IC50 around 3.8 pM by model fit without a high-concentration plateau and maximal response of 65% inhibition at the highest concentration tested (10 pM), [FIG. 36],

[0310] Example 7: AMY3 Cell Based cAMP TR-FRET AssayAttorney Docket No. 130948.00011

[0311] Bromantane agonist activity at the human amylin subtype 3 (AMY3) receptor complex (CALCR-RAMP3) was evaluated with a cell based functional assay that quantifies intracellular cAMP using a time resolved fluorescence resonance energy transfer (TR-FRET) readout. The assay used a CH0-K1 cell line expressing the human receptor target and signaling through a Gs coupled pathway, and it was run in agonist mode to assess receptor mediated stimulation of cAMP. Cells in assay buffer with 500 pM 1BMX were dispensed into a well plate at the appropriate density, 5 pL per well. Bromantane stock solution was prepared at 10 mM in DMSO and assays were performed in duplicate in 10-point concentration response format over a final assay concentration range of 0.0005 to 10 pM. A serial dilution of bromantane was prepared in assay buffer at 2x and added to cells in a 5 pL volume to achieve the desired final assay concentrations. Hie final vehicle (DMSO) concentration in wells was 1%. Following addition of compound, plates were incubated at 37°C or room temperature for 30 or 60 minutes.

[0312] Intracellular cAMP was quantified using a competitive TR-FRET cAMP detection fomiat in which native cAMP produced by cells competes with a d2 labeled cAMP tracer for binding to a monoclonal anti-cAMP antibody labeled with a Eu3+cryptate donor. Calcitonin was used as the reference agonist control. For this Gs agonist format, responses were normalized as percent activity relative to vehicle (baseline) and a maximal control ligand condition: % Activity = 100 x (Mean Ratio test - Mean Ratio_vehicle) / (Mean Ratio MAX - Mean Ratio_vehicle). Concentration response curves were fit by nonlinear regression to estimate EC50 values and associated curve parameters. Bromantane produced an agonist response with an apparent EC50 of 3.9 pM by model fit without a high -concentration plateau and maximal response of 57% activity at the highest concentration tested (10 pM) [FIG. 35],

[0313] While the invention is described in terms of particular embodiments and applications, it is not intended that these descriptions in any way limit its scope to any such embodiments and applications, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention can be made by those skilled in the art without departing from the spirit or scope of the invention. Similarly, the exemplary embodiments illustrated in referenced figures are intended to be illustrative rather than restrictive. The aim of this disclosure is to provide an understanding of the invention to a person with ordinary skill in the art. Well known elements are not described in detail to avoid unnecessarily obscuring the disclosure.

Claims

Attorney Docket No. 130948.00011CLAIMS1. A method of treating stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein said stimulant use disorder or stimulant withdrawal is influenced by maladaptive learning.

3. A method of treating a disorder of maladaptive learning, the method comprising:assessing a subject in need thereof suffering from symptoms of a mental disorder or syndrome to detennine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; andfacilitating extinction learning in the subject in need thereof by administering a therapeutically effective amount of a pharmacal preparation of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

4. Tire method of any one of claims 1-3, wherein the subject in need thereof suffers from the disorder of maladaptive learning and optionally a disorder selected from oppositional defiant disorder, intennittent explosive disorder, kleptomania, pyromania, post-traumatic stress disorder, acute stress disorder, complex post-traumatic stress disorder, adjustment disorders, generalized anxiety disorder, panic disorder, social anxiety disorder, phobias, obsessive-compulsive disorder, major depressive disorder, persistent depressive disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, orthorexia nervosa, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, somatic symptom disorder, illness anxiety disorder, conversion disorder, depersonalization-derealization disorder, dissociative identity disorder, or combinations thereof.

5. Tire method of any one of claims 1-4, wherein the subject in need thereof suffers from the disorder of maladaptive learning and a disorder selected from oppositional defiant disorder, intermittent explosive disorder, kleptomania, pyromania, post-traumatic stress disorder, acute stress disorder, complex post-traumatic stress disorder, adjustment disorders, generalized anxiety disorder, panic disorder, social anxiety disorder, phobias, obsessive-compulsive disorder, major depressive disorder, persistent depressive disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, orthorexia nervosa, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsiveAttorney Docket No. 130948.00011personality disorder, somatic symptom disorder, illness anxiety disorder, conversion disorder, depersonalization-derealization disorder, dissociative identity disorder, or combinations thereof.

6. The method of any one of claims 1-3, wherein the subject in need thereof suffers from the disorder of maladaptive learning and optionally a syndrome selected from substance withdrawal syndrome, stress-related syndrome, trauma-related syndrome, anxiety -related syndrome, circadian rhythm-related syndrome, mood-related syndrome, somatization syndrome, impulse control syndrome, or combinations thereof7. The method of claim 6, wherein the syndrome is a substance withdrawal syndrome.

8. Tire method of claim 7, wherein the substance withdrawal syndrome is stimulant withdrawal.

9. The method of any one of claims 1-5, wherein the disorder of maladaptive learning is a substance use disorder.

10. The method of claim 9, wherein the substance use disorder is stimulant use disorder.

11. The method of claim 8-10, wherein the substance withdrawal syndrome is associated with a substance selected from antidepressants, anxiolytics, sedatives, anesthetics, antipsychotics, stimulants, and pain medications.

12. The method of any one of claims 1-11, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered as a single -agent therapeutic.

13. The method of any one of claims 1-11, the therapeutically effective amount is administered only once per day and without any administering of a secondary therapeutic agent.

14. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 7 days.

15. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 14 days.

16. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg qd for 21 days.

17. The method of any one of claims 1-13, wherein the bromantane. the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 7 days.Attorney Docket No. 130948.0001118. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 14 days.

19. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 21 days.

20. The method of any one of claims 1-13, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 7 days.

21. The method of any one of claims 1-20, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase.

22. The method of any one of claims 1-21, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a complex dosing regimen comprising an induction phase followed by a discontinuation phase, wherein the amount administered qd during the induction phase is greater than the amount administered qd during the discontinuation phase.

23. The method of any one of claim 21, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days.

24. The method of any one of claim 21, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 100 mg qd for 3-14 days during the induction phase and administered in a dose of 50 mg qd for 1-60 days during the discontinuation phase.

25. The method of any one of claim 21, wherein the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg qd for 3-14 days during the induction phase and administered in a dose of 40 mg qd for 1-60 days during the discontinuation phase.

26. The method of any one of claim 21, wherein (a) the bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, is administered in a dose of (al) 100 mg qd for 3-14 days; (a2) 80 mg qd for 3-14 days; (a3) 50 mg qd for 3-14 days; (a4) 40 mg qd for 3-14 days; (a5) 30 mg qd for 3-14 days; or (a4) 20 mg qd for 3-14 days; during the induction phase; and wherein (b) the bromantane, analogue thereof, or the pharmaceutically acceptable salt thereof, is administered over a tapered schedule during the discontinuation phase.Attorney Docket No. 130948.0001127. The method of any one of claims 1-26, further comprising administering an adjunctive psychotherapy to the subject in need thereof, wherein the adjunctive psychotherapy facilitates the development of adaptive responses in the subject.

28. The method of any one of claims 1-26, further comprising prior to administering the therapeutically effective amount, assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms.

29. The method of any of claims 1-28, wherein the subject in need thereof is a pediatric male or female.

30. The method of any of claims 1-28. wherein the subject in need thereof is an adolescent male or female.

31. The method of any of claims 1-28, wherein the subject in need thereof is a teen male or female.

32. The method of any of claims 1-31. wherein the subject in need thereof are administered or have been administered attention-deficit / hyperactivity disorder (ADHD) medications.

33. Tire method of claim 32, wherein the ADHD medication is methylphenidate, amphetamine, or combinations thereof.

34. A method of treating a disorder of maladaptive learning, the method comprising:a. assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; andb. facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,Attorney Docket No. 130948.00011or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Rl, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, R5, and R6, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring, wherein the fused 5-member ring is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole. isothiazole, pyrazole. triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane; andL is independently selected from amine, amide, or imine.

35. The method of Claim 34, wherein L is amine.

36. The method of Claim 34, wherein L is amide.

37. The method of Claim 34, wherein L is imine.

38. A method of treating a disorder of maladaptive learning, the method comprising:facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of bromantane, or an analogue of bromantane, having a chemical structure according to Formula I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Ri, R2, and R3 are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;Attorney Docket No. 130948.00011R4, RS, and Re, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring, wherein the fused 5-member ring is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole. triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane; andL is independently selected from amine, amide, or imine.

39. A method of treating a disorder of maladaptive learning, the method comprising:facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of an analogue of bromantane having a chemical structure according to Formula I.I,or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a phenyl ring (B) by a linker (L);Ri, R2, and Rj are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl;R4, Rs, and Re, are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5-member ring, wherein the fused 5-member ring is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole. isothiazole, pyrazole. triazole, tetrazole, oxadiazole, thiadiazole, dioxole, oxathiolane, or dithiolane;L is independently selected from amine, amide, or imine; andthe chemical structure differs in at least one substituent (Ri, R2, Rs, R4, Rs, Re, or L) such that it is structurally distinct from bromantane.Attorney Docket No. 130948.0001140. The method of Claim 39, wherein L is amine.

41. The method of Claim 39, wherein L is amide.

42. The method of Claim 39, wherein L is imine.

43. A method of modulating a network of receptors, the method comprising:facilitating extinction learning in the subject in need thereof by administering to the subject a therapeutically effective amount of bromantane, an analogue thereof, or a pharmaceutically acceptable salt thereof,wherein the receptors are selected from human cannabinoid receptor 2 (CB2), androgen receptor (AR), amylin receptor subtype 3 (AMY3), orexin receptor 2 (0X2), or combinations thereof.

44. The method of claim 43, comprising administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to agonize the CB2 receptor.

45. The method of claim 43, comprising administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to antagonize the AR receptor.

46. The method of claim 43. comprising administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to agonize the AMY3 receptor.

47. The method of claim 43. comprising administering a therapeutically effective amount of bromantane, the analogue thereof, or the pharmaceutically acceptable salt thereof, to antagonize the 0X2 receptor.

48. A pharmaceutical preparation comprising:a. a therapeutically effective amount of bromantane, or an analogue thereof, as a drug substance in the form of a salt, solvate, complex, or conjugate: andb. one or more pharmaceutically acceptable excipients that inhibit crystallization, wherein, the morphology of the drug substance is amorphous.

49. A pharmaceutical preparation comprising:a. a therapeutically effective amount of bromantane in amorphous free base form; andb. one or more pharmaceutically acceptable excipients.

50. The pharmacal preparation of claim of 48 or 49, wherein the bromantane is present in an amorphous solid dispersion.Attorney Docket No. 130948.0001151. The pharmaceutical preparation of claim 48 or 49, wherein the pharmaceutically acceptable excipient that functions to inhibit crystallization contains a functional group selected from the group consisting of sulfate, phosphate, and carboxylate.

52. The pharmaceutical preparation of claim 51, wherein the pharmaceutically acceptable excipient that inhibits crystallization contains a carboxylate.

53. The pharmaceutical preparation of claim 48 or 49. wherein tire pharmaceutical preparation is a tablet dosage form comprising 20 mg to 200 mg of an amorphous solid dispersion of bromantane in copovidone, wherein bromantane is present in the Amorphous Solid Dispersion at 30 %w / w to 80 %w / w.

54. The pharmaceutical preparation of claims 48 or 49, wherein the pharmaceutical preparation is an oral thin film comprising: 20 mg to 80 mg of amorphous bromantane and 20 mg to 150 mg of pullulan.

55. A method of treating a comorbidity associated with stimulant use disorder or stimulant withdrawal in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bromantane, or an analogue of bromantane. or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein the comorbidity is attention deficit hyperactivity disorder (ADHD).

57. The method of claim 55. wherein the comorbidity is a stress-related syndrome.

58. The method of claim 55, wherein the comorbidity is selected from anxiety, depression, personality disorders, or combinations thereof.

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